15.14: Fungal Diseases of the Respiratory System - Biology

15.14: Fungal Diseases of the Respiratory System - Biology

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15.14: Fungal Diseases of the Respiratory System

Defense Mechanisms of the Respiratory System

The average person who is moderately active during the daytime breathes about 20,000 liters (more than 5,000 gallons) of air every 24 hours. Inevitably, this air (which would weigh more than 20 kilograms [44 pounds]) contains potentially harmful particles and gases. Particles, such as dust and soot, mold, fungi, bacteria, and viruses deposit on airway and alveolar surfaces. Fortunately, the respiratory system has defense mechanisms to clean and protect itself. Only extremely small particles, less than 3 to 5 microns (0.000118 to 0.000196 inches) in diameter, penetrate to the deep lung.

Cilia, tiny muscular, hair-like projections on the cells that line the airway, are one of the respiratory system's defense mechanisms. Cilia propel a liquid layer of mucus that covers the airways.

The mucus layer traps pathogens (potentially infectious microorganisms) and other particles, preventing them from reaching the lungs.

Cilia beat more than 1,000 times a minute, moving the mucus that lines the trachea upwards about 0.5 to 1 centimeter per minute (0.197 to 0.4 inch per minute). Pathogens and particles that are trapped on the mucus layer are coughed out or moved to the mouth and swallowed.

Alveolar macrophages, a type of white blood cell on the surface of alveoli, are another defense mechanism for the lungs. Because of the requirements of gas exchange, alveoli are not protected by mucus and cilia—mucus is too thick and would slow movement of oxygen and carbon dioxide. Instead, alveolar macrophages seek out deposited particles, bind to them, ingest them, kill any that are living, and digest them. When the lungs are exposed to serious threats, additional white blood cells in the circulation, especially neutrophils, can be recruited to help ingest and kill pathogens. For example, when the person inhales a great deal of dust or is fighting a respiratory infection, more macrophages are produced and neutrophils are recruited.

(p. 205) Fungal diseases of the respiratory tract

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Fungal respiratory infections are important causes of morbidity and mortality in immunocompromised patients. Invasive aspergillosis remains the most common invasive fungal infection whereas other filamentous fungi, such as Fusarium spp., Mucorales, and Scedosporium spp., are increasing in frequency, particularly in neutropenic hosts. Endemic mycoses, including those due to Histoplasma capsulatum, Coccidioides spp., and Talaromyces marneffei, are increasingly prevalent in patients with cell-mediated immunodeficiencies in respective geographic regions. Culture remains the gold standard of diagnosis but has limited sensitivity and often requires invasive procedures. Non-invasive diagnostic tests, including the serum sandwich enzyme immunoassay for the detection of galactomannan, the (1→3)-β‎-D-glucan assay, and molecular amplification methods have been developed to facilitate early and accurate diagnosis. Successful therapy depends upon early initiation of antifungal agents and reversal of immunosuppression. Lipid formulations of amphotericin B and newer generation triazoles including voriconazole, posaconazole, and isavuconazole have expanded the ability to treat multi-drug resistant pathogens more effectively and with less toxicity.

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Modes of survival

Infectious agents have various methods of survival. Some depend on rapid multiplication and rapid spread from one host to another. For example, when the measles virus enters the body, it multiplies for a week or two and then enters the bloodstream and spreads to every organ. For several days before a rash appears, the surface cells of the respiratory tract are bursting with measles virus, and vast quantities are shed every time the infected person coughs or sneezes. A day or two after the rash appears, the amount of antibody (protein produced in response to a pathogen) rises in the bloodstream, neutralizing the virus and stopping further shedding. The patient rapidly becomes noninfectious but already may have spread the virus to others. In this way an epidemic can rapidly occur. Many other infectious agents—for example, influenza virus—survive in this manner. How such viruses exist between epidemics is, in some cases, less clear.

The picture is different in more-chronic infections. In tuberculosis there is neither overwhelming multiplication nor rapid shedding of the tubercle bacillus. Rather, the bacilli remain in the infected person’s body for a long period, slowly forming areas of chronic inflammation that may from time to time break down and allow them to escape.

Some organisms form spores, a resting or dormant stage that is resistant to heat, cold, drying, and chemical action. Spore-forming organisms can survive for months or years under the most adverse conditions and may not, in fact, be highly infectious. The bacterium that causes tetanus, Clostridium tetani, is present everywhere in the environment—in soil, in dust, on window ledges and floors—and yet tetanus is an uncommon disease, especially in developed countries. The same is true of the anthrax bacterium, Bacillus anthracis. Although usually present in abundance in factories in which rawhides and animal wool and hair are handled, it rarely causes anthrax in employees. Clostridium botulinum, the cause of botulism, produces one of the most lethal toxins that can afflict humans, and yet the disease is one of the rarest because the microorganism depends for its survival on its resistant spore.

In contrast to these relatively independent organisms, there are others that cannot exist at all outside the human body. The germs of syphilis and gonorrhea, for example, depend for survival on their ability to infect and their adaptation to the human environment.

Some organisms have complicated life cycles and depend on more than one host. The malarial parasite must spend a portion of its life cycle inside a mosquito, while the liver fluke Fasciola hepatica, an occasional human parasite, spends part of its life in the body of a land animal such as a sheep, part in a water snail, and part in the open air as a cyst attached to grass.

Upper Respiratory Infections

Infections of the respiratory tract are grouped according to their symptomatology and anatomic involvement. Acute upper respiratory infections (URI) include the common cold, pharyngitis, epiglottitis, and laryngotracheitis (Fig. 93-1). These infections are usually benign, transitory and self-limited, altho ugh epiglottitis and laryngotracheitis can be serious diseases in children and young infants. Etiologic agents associated with URI include viruses, bacteria, mycoplasma and fungi (Table 93-1). Respiratory infections are more common in the fall and winter when school starts and indoor crowding facilitates transmission.

Figure 93-1

Upper and lower respiratory tract infections.

Common Cold


Common colds are the most prevalent entity of all respiratory infections and are the leading cause of patient visits to the physician, as well as work and school absenteeism. Most colds are caused by viruses. Rhinoviruses with more than 100 serotypes are the most common pathogens, causing at least 25% of colds in adults. Coronaviruses may be responsible for more than 10% of cases. Parainfluenza viruses, respiratory syncytial virus, adenoviruses and influenza viruses have all been linked to the common cold syndrome. All of these organisms show seasonal variations in incidence. The cause of 30% to 40% of cold syndromes has not been determined.


The viruses appear to act through direct invasion of epithelial cells of the respiratory mucosa (Fig. 93-2), but whether there is actual destruction and sloughing of these cells or loss of ciliary activity depends on the specific organism involved. There is an increase in both leukocyte infiltration and nasal secretions, including large amounts of protein and immunoglobulin, suggesting that cytokines and immune mechanisms may be responsible for some of the manifestations of the common cold (Fig. 93-3).

Figure 93-2

Pathogenesis of viral and bacterial mucosal respiratory infections.

Figure 93-3

Pathogenesis of upper respiratory tract infections.

Clinical Manifestations

After an incubation period of 48� hours, classic symptoms of nasal discharge and obstruction, sneezing, sore throat and cough occur in both adults and children. Myalgia and headache may also be present. Fever is rare. The duration of symptoms and of viral shedding varies with the pathogen and the age of the patient. Complications are usually rare, but sinusitis and otitis media may follow.

Microbiologic Diagnosis

The diagnosis of a common cold is usually based on the symptoms (lack of fever combined with symptoms of localization to the nasopharynx). Unlike allergic rhinitis, eosinophils are absent in nasal secretions. Although it is possible to isolate the viruses for definitive diagnosis, that is rarely warranted.

Prevention and Treatment

Treatment of the uncomplicated common cold is generally symptomatic. Decongestants, antipyretics, fluids and bed rest usually suffice. Restriction of activities to avoid infecting others, along with good hand washing, are the best measures to prevent spread of the disease. No vaccine is commercially available for cold prophylaxis.


Sinusitis is an acute inflammatory condition of one or more of the paranasal sinuses. Infection plays an important role in this affliction. Sinusitis often results from infections of other sites of the respiratory tract since the paranasal sinuses are contiguous to, and communicate with, the upper respiratory tract.


Acute sinusitis most often follows a common cold which is usually of viral etiology. Vasomotor and allergic rhinitis may also be antecedent to the development of sinusitis. Obstruction of the sinusal ostia due to deviation of the nasal septum, presence of foreign bodies, polyps or tumors can predispose to sinusitis. Infection of the maxillary sinuses may follow dental extractions or an extension of infection from the roots of the upper teeth. The most common bacterial agents responsible for acute sinusitis are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Other organisms including Staphylococcus aureus, Streptococcus pyogenes, gram-negative organisms and anaerobes have also been recovered. Chronic sinusitis is commonly a mixed infection of aerobic and anaerobic organisms.


Infections caused by viruses or bacteria impair the ciliary activity of the epithelial lining of the sinuses and increased mucous secretions. This leads to obstruction of the paranasal sinusal ostia which impedes drainage. With bacterial multiplication in the sinus cavities, the mucus is converted to mucopurulent exudates. The pus further irritates the mucosal lining causing more edema, epithelial destruction and ostial obstruction. When acute sinusitis is not resolved and becomes chronic, mucosal thickening results and the development of mucoceles and polyps may ensue.

Clinical Manifestations

The maxillary and ethmoid sinuses are most commonly involved in sinusitis. The frontal sinuses are less often involved and the sphenoid sinuses are rarely affected. Pain, sensation of pressure and tenderness over the affected sinus are present. Malaise and low grade fever may also occur. Physical examination usually is not remarkable with no more than an edematous and hyperemic nasal mucosa.

In uncomplicated chronic sinusitis, a purulent nasal discharge is the most constant finding. There may not be pain nor tenderness over the sinus areas. Thickening of the sinus mucosa and a fluid level are usually seen in x-ray films or magnetic resonance imaging.

Microbiologic Diagnosis

For acute sinusitis, the diagnosis is made from clinical findings. A bacterial culture of the nasal discharge can be taken but is not very helpful as the recovered organisms are generally contaminated by the resident flora from the nasal passage. In chronic sinusitis, a careful dental examination, with sinus x-rays may be required. An antral puncture to obtain sinusal specimens for bacterial culture is needed to establish a specific microbiologic diagnosis.

Prevention and Treatment

Symptomatic treatment with analgesics and moist heat over the affected sinus pain and a decongestant to promote sinus drainage may suffice. For antimicrobial therapy, a beta-lactamase resistant antibiotic such as amoxicillin-clavulanate or a cephalosporin may be used. For chronic sinusitis, when conservative treatment does not lead to a cure, irrigation of the affected sinus may be necessary. Culture from an antral puncture of the maxillary sinus can be performed to identify the causative organism for selecting antimicrobial therapy. Specific preventive procedures are not available. Proper care of infectious and/or allergic rhinitis, surgical correction to relieve or avoid obstruction of the sinusal ostia are important. Root abscesses of the upper teeth should receive proper dental care to avoid secondary infection of the maxillary sinuses.


Infections of the ears are common events encountered in medical practice, particularly in young children. Otitis externa is an infection involving the external auditory canal while otitis media denotes inflammation of the middle ear.


For otitis externa, the skin flora such as Staphylococcus epidermidis, Staphylococcus aureus, diphtheroids and occasionally an anaerobic organism, Propionibacterium acnes are major etiologic agents. In a moist and warm environment, a diffuse acute otitis externa (Swimmer's ear) may be caused by Pseudomonas aeruginosa, along with other skin flora. Malignant otitis externa is a severe necrotizing infection usually caused by Pseudomonas aeruginosa.

For otitis media, the commonest causative bacteria are Streptococcus pneumoniae, Hemophilus influenzae and beta-lactamase producing Moraxella catarrhalis. Respiratory viruses may play a role in otitis media but this remains uncertain. Mycoplasma pneumoniae has been reported to cause hemorrhagic bullous myringitis in an experimental study among nonimmune human volunteers inoculated with M pneumoniae. However, in natural cases of M pneumoniae infection, clinical bullous myringitis or otitis media is uncommon.


The narrow and tortuous auditory canal is lined by a protective surface epithelium. Factors that may disrupt the natural protective mechanisms, such as high temperature and humidity, trauma, allergy, tissue maceration, removal of cerumen and an alkaline pH environment, favor the development of otitis externa. Prolonged immersion in a swimming pool coupled with frequent ear cleansing increases the risk of otitis externa.

Acute otitis media commonly follows an upper respiratory infection extending from the nasopharynx via the eustachian tube to the middle ear. Vigorous nose blowing during a common cold, sudden changes of air pressure, and perforation of the tympanic membrane also favor the development of otitis media. The presence of purulent exudate in the middle ear may lead to a spread of infection to the inner ear and mastoids or even meninges

Clinical Manifestations

Otitis externa

Furuncles of the external ear, similar to those in skin infection, can cause severe pain and a sense of fullness in the ear canal. When the furuncle drains, purulent otorrhea may be present. In generalized otitis externa, itching, pain and tenderness of the ear lobe on traction are present. Loss of hearing may be due to obstruction of the ear canal by swelling and the presence of purulent debris.

Malignant otitis externa tends to occur in elderly diabetic patients. It is characterized by severe persistent earache, foul smelling purulent discharge and the presence of granulation tissue in the auditory canal. The infection may spread and lead to osteomyelitis of the temporal bone or externally to involve the pinna with osteochondritis.

Otitis media

Acute otitis media occurs most commonly in young children. The initial complaint usually is persistent severe earache (crying in the infant) accompanied by fever, and, and vomiting. Otologic examination reveals a bulging, erythematous tympanic membrane with loss of light reflex and landmarks. If perforation of the tympanic membrane occurs, serosanguinous or purulent discharge may be present. In the event of an obstruction of the eustachian tube, accumulation of a usually sterile effusion in the middle ear results in serous otitis media. Chronic otitis media frequently presents a permanent perforation of the tympanic membrane. A central perforation of the pars tensa is more benign. On the other hand, an attic perforation of the pars placcida and marginal perforation of the pars tensa are more dangerous and often associated with a cholesteatoma.


The diagnosis of both otitis externa and otitis media can be made from history, clinical symptomatology and physical examinations. Inspection of the tympanic membrane is an indispensable skill for physicians and health care workers. All discharge, ear wax and debris must be removed and to perform an adequate otoscopy. In the majority of patients, routine cultures are not necessary, as a number of good bacteriologic studies have shown consistently the same microbial pathogens mentioned in the section of etiology. If the patient is immunocompromised or is toxic and not responding to initial antimicrobial therapy tympanocentesis (needle aspiration) to obtain middle ear effusion for microbiologic culture is indicated.

Prevention and Treatment

Otitis externa

Topical therapy is usually sufficient and systemic antimicrobials are seldom needed unless there are signs of spreading cellulitis and the patient appears toxic. A combination of topical antibiotics such as neomycin sulfate, polymyxin B sulfate and corticosteroids used as eardrops, is a preferred therapy. In some cases, acidification of the ear canal by applying a 2% solution of acetic acid topically may also be effective. If a furuncle is present in the external canal, the physician should allow it to drain spontaneously.

Otitis media

Amoxicillin is an effective and preferred antibiotic for treatment of acute otitis media. Since beta-lactamase producing H influenzae and M catarrhalis can be a problem in some communities, amoxicillin-clavulanate is used by many physicians. Oral preparations of trimethoprim/sulfamethoxazole, second and third generation cephalosporins, tetracyclines and macrolides can also be used. When there is a large effusion, tympanocentesis may hasten the resolution process by decreasing the sterile effusion. Patients with chronic otitis media and frequent recurrences of middle ear infections may be benefitted by chemoprophylaxis with once daily oral amoxicillin or trimethoprim/sulfamethoxazole during the winter and spring months. In those patients with persistent effusion of the middle ear, surgical interventions with myringotomy, adenoidectomy and the placement of tympanotomy tubes has been helpful.

Use of polyvalent pneumococcal vaccines has been evaluated for the prevention of otitis media in children. However, children under two years of age do not respond satisfactorily to polysaccharide antigens further, no significant reduction in the number of middle ear infections was demonstrable. Newer vaccines composed of pneumococcal capsular polysaccharides conjugated to proteins may increase the immunogenicity and are currently under clinical investigation for efficacy and safety.



Pharyngitis is an inflammation of the pharynx involving lymphoid tissues of the posterior pharynx and lateral pharyngeal bands. The etiology can be bacterial, viral and fungal infections as well as noninfectious etiologies such as smoking. Most cases are due to viral infections and accompany a common cold or influenza. Type A coxsackieviruses can cause a severe ulcerative pharyngitis in children (herpangina), and adenovirus and herpes simplex virus, although less common, also can cause severe pharyngitis. Pharyngitis is a common symptom of Epstein-Barr virus and cytomegalovirus infections.

Group A beta-hemolytic streptococcus or Streptococcus pyogenes is the most important bacterial agent associated with acute pharyngitis and tonsillitis. Corynebacterium diphtheriae causes occasional cases of acute pharyngitis, as do mixed anaerobic infections (Vincent's angina), Corynebacterium haemolyticum, Neisseria gonorrhoeae, and Chlamydia trachomatis. Outbreaks of Chlamydia pneumoniae (TWAR agent) causing pharyngitis or pneumonitis have occurred in military recruits. Mycoplasma pneumoniae and Mycoplasma hominis have been associated with acute pharyngitis. Candida albicans, which causes oral candidiasis or thrush, can involve the pharynx, leading to inflammation and pain.


As with common cold, viral pathogens in pharyngitis appear to invade the mucosal cells of the nasopharynx and oral cavity, resulting in edema and hyperemia of the mucous membranes and tonsils (Fig 93-2). Bacteria attach to and, in the case of group A beta-hemolytic streptococci, invade the mucosa of the upper respiratory tract. Many clinical manifestations of infection appear to be due to the immune reaction to products of the bacterial cell. In diphtheria, a potent bacterial exotoxin causes local inflammation and cell necrosis.

Clinical Manifestations

Pharyngitis usually presents with a red, sore, or “scratchy” throat. An inflammatory exudate or membranes may cover the tonsils and tonsillar pillars. Vesicles or ulcers may also be seen on the pharyngeal walls. Depending on the pathogen, fever and systemic manifestations such as malaise, myalgia, or headache may be present. Anterior cervical lymphadenopathy is common in bacterial pharyngitis and difficulty in swallowing may be present.

Microbiologic Diagnosis

The goal in the diagnosis of pharyngitis is to identify cases that are due to group A beta-hemolytic streptococci, as well as the more unusual and potentially serious infections. The various forms of pharyngitis cannot be distinguished on clinical grounds. Routine throat cultures for bacteria are inoculated onto sheep blood and chocolate agar plates. Thayer-Martin medium is used if N gonorrhoeae is suspected. Viral cultures are not routinely obtained for most cases of pharyngitis. Serologic studies may be used to confirm the diagnosis of pharyngitis due to viral, mycoplasmal or chlamydial pathogens. Rapid diagnostic tests with fluorescent antibody or latex agglutination to identify group A streptococci from pharyngeal swabs are available. Gene probe and polymerase chain reaction can be used to detect unusual organisms such as M pneumoniae, chlamydia or viruses but these procedures are not routine diagnostic methods.

Prevention and Treatment

Symptomatic treatment is recommended for viral pharyngitis. The exception is herpes simplex virus infection, which can be treated with acyclovir if clinically warranted or if diagnosed in immunocompromised patients. The specific antibacterial agents will depend on the causative organism, but penicillin G is the therapy of choice for streptococcal pharyngitis. Mycoplasma and chlamydial infections respond to erythromycin, tetracyclines and the new macrolides.

Epiglottitis and Laryngotracheitis


Inflammation of the upper airway is classified as epiglottitis or laryngotracheitis (croup) on the basis of the location, clinical manifestations, and pathogens of the infection. Haemophilus influenzae type b is the most common cause of epiglottitis, particularly in children age 2 to 5 years. Epiglottitis is less common in adults. Some cases of epiglottitis in adults may be of viral origin. Most cases of laryngotracheitis are due to viruses. More serious bacterial infections have been associated with H influenzae type b, group A beta-hemolytic streptococcus and C diphtheriae. Parainfluenza viruses are most common but respiratory syncytial virus, adenoviruses, influenza viruses, enteroviruses and Mycoplasma pneumoniae have been implicated.


A viral upper respiratory infection may precede infection with H influenzae in episodes of epiglottitis. However, once H influenzae type b infection starts, rapidly progressive erythema and swelling of the epiglottis ensue, and bacteremia is usually present. Viral infection of laryngotracheitis commonly begins in the nasopharynx and eventually moves into the larynx and trachea. Inflammation and edema involve the epithelium, mucosa and submucosa of the subglottis which can lead to airway obstruction.

Clinical Manifestations

The syndrome of epiglottitis begins with the acute onset of fever, sore throat, hoarseness, drooling, dysphagia and progresses within a few hours to severe respiratory distress and prostration. The clinical course can be fulminant and fatal. The pharynx may be inflamed, but the diagnostic finding is a 𠇌herry-red” epiglottis.

A history of preceding cold-like symptoms is typical of laryngotracheitis, with rhinorrhea, fever, sore throat and a mild cough. Tachypnea, a deep barking cough and inspiratory stridor eventually develop. Children with bacterial tracheitis appear more ill than adults and are at greater risk of developing airway obstruction.

Haemophilus influenzae type b is isolated from the blood or epiglottis in the majority of patients with epiglottis therefore a blood culture should always be performed. Sputum cultures or cultures from pharyngeal swabs may be used to isolate pathogens in patients with laryngotracheitis. Serologic studies to detect a rise in antibody titers to various viruses are helpful for retrospective diagnosis. Newer, rapid diagnostic techniques, using immunofluorescent-antibody staining to detect virus in sputum, pharyngeal swabs, or nasal washings, have been successfully used. Enzyme-linked immunosorbent assay (ELISA), DNA probe and polymerase chain reaction procedures for detection of viral antibody or antigens are now available for rapid diagnosis.

Prevention and Treatment

Epiglottitis is a medical emergency, especially in children. All children with this diagnosis should be observed carefully and be intubated to maintain an open airway as soon as the first sign of respiratory distress is detected. Antibacterial therapy should be directed at H influenzae. Patients with croup are usually successfully managed with close observation and supportive care, such as fluid, humidified air, and racemic epinephrine. For prevention, Haemophilus influenzae type b conjugated vaccine is recommended for all pediatric patients, as is immunization against diphtheria.


Several recent studies and international reports estimated the huge global health burden of CRDs and other major NCDs, pointing out the need for implementing international collaborations to fight this epidemic trend.

The Global Alliance Against Chronic Respiratory Diseases (GARD) is an alliance of WHO and national and international organizations, medical and scientific societies, institutions and agencies, all working with the common goal of reducing the global burden of CRDs. The concept of GARD is a world where all people breathe freely. To achieve this goal, GARD has defined four strategic objectives: (41)

Advocacy. To raise the recognition of the importance of CRDs at global and country levels, and to advocate the integration of the prevention and control of such diseases into policies across all government departments

I) Partnership. To promote partnering for the prevention and control of CRDs

II) National plans on prevention and control. To support WHO in assisting countries to establish and strengthen national policies and plans for the prevention and control of CRDs using WHO-endorsed approaches and methods

V) Surveillance. To support WHO in monitoring CRDs and their determinants and to evaluate progress at country, regional, and global levels.

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