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InternalMed_Harrison. B. fragilis produces other virulence factors that allow it to predominate in disease. This organism synthesizes pili, fimbriae, and hemagglutinins that aid in attachment to host cell surfaces. In addition, Bacteroides species produce many enzymes and toxins that contribute to pathogenicity. Enzymes such as neuraminidase, protease, glycoside hydrolases, and superoxide dismutases are all produced by B. fragilis. Anaerobic bacteria produce a number of exoproteins that can enhance the organisms’ virulence. The collagenase produced by


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InternalMed_Harrison. B. fragilis. Anaerobic bacteria produce a number of exoproteins that can enhance the organisms’ virulence. The collagenase produced by P. gingivalis may enhance tissue destruction. An association of B. fragilis strains positive for the enterotoxin BFT with clinical episodes of diarrhea in children and adults has been suggested. BFT is a metalloprotease that is cytopathic for intestinal epithelial cells and induces fluid secretion and tissue damage in ligated intestinal loops of experimental animals. Recent evidence from mouse models indicates that enterotoxin-producing strains of B. fragilis may play a role in colon carcinoma.


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InternalMed_Harrison. Exotoxins produced by clostridial species, including botulinum toxins, tetanus toxin, C. difficile toxins A and B, and five toxins produced by Clostridium perfringens, are among the most virulent bacterial toxins in mouse lethality assays. Anaerobic gram-negative bacteria such as B. fragilis possess LPSs (endotoxins) that are 100–1000 times less biologically potent than endotoxins associated with aerobic gram-negative bacteria. This relative biologic inactivity may account for the lower frequency of disseminated intravascular coagulation and purpura in Bacteroides bacteremia than in facultative and aerobic gram-negative bacillary bacteremia. An exception is the LPS from Fusobacterium, which may account for the severity of Lemierre’s syndrome (see “Complications of Anaerobic Head and Neck Infections,” below). APPROACH TO THE PATIENT: Infection due to Anaerobic Bacteria


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InternalMed_Harrison. APPROACH TO THE PATIENT: Infection due to Anaerobic Bacteria The physician must consider several points when approaching the patient with possible infection due to anaerobic bacteria. 1. Most of the organisms colonizing mucosal sites are commensals; very few cause disease. When these organisms do cause disease, it often occurs in proximity to the mucosal site they colonize. 2. For anaerobes to cause tissue infection, they must spread beyond the normal mucosal barriers. 3. Conditions favoring the propagation of anaerobic bacteria, particularly a lowered oxidation-reduction potential, are necessary. These conditions exist at sites of trauma, tissue destruction, compromised vascular supply, and complications of preexisting infection, which produce necrosis. 4. Frequently, a complex array of infecting microbes can be found. For example, as many as 12 species of organisms can be isolated from a suppurative site. 5.


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InternalMed_Harrison. 4. Frequently, a complex array of infecting microbes can be found. For example, as many as 12 species of organisms can be isolated from a suppurative site. 5. Anaerobic organisms tend to be found in abscess cavities or in necrotic tissue. The failure of an abscess to yield organisms on routine culture is a clue that the abscess is likely to contain anaerobic bacteria. Often smears of this “sterile pus” are found to be teeming with bacteria when Gram’s stain is applied. Although some facultative organisms (e.g., Staphylococcus aureus) are also capable of causing abscesses, abscesses in organs or deeper body tissues should call anaerobic infection to mind. 6. Gas is found in many anaerobic infections of deep tissues but is not diagnostic because it can be produced by aerobic bacteria as well. 7.


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InternalMed_Harrison. 6. Gas is found in many anaerobic infections of deep tissues but is not diagnostic because it can be produced by aerobic bacteria as well. 7. Although a putrid-smelling infection site or discharge is considered diagnostic for anaerobic infection, this manifestation usually develops late in the course and is present in only 30–50% of cases. 8. Some species (the best example being the B. fragilis group) require specific therapy. However, many synergistic infections can be cured with antibiotics directed at some but not all of the organisms involved. Antibiotic therapy, combined with debridement and drainage, disrupts the interdependent relationship among the bacteria, and some species that are resistant to the antibiotic do not survive without the co-infecting organisms. 9. Manifestations of severe sepsis and disseminated intravascular coagulation are unusual in patients with purely anaerobic infection.


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InternalMed_Harrison. 9. Manifestations of severe sepsis and disseminated intravascular coagulation are unusual in patients with purely anaerobic infection. Difficulties in the performance of appropriate cultures, contamination of cultures by components of the normal microbiota, and the lack of readily available, reliable culture techniques have made it impossible to obtain accurate data on incidence or prevalence. However, anaerobic infections are encountered frequently in hospitals with active surgical, trauma, and obstetric and gynecologic services. Depending on the institution, anaerobic bacteria account for 0.5–12% of all cases of bacteremia.


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InternalMed_Harrison. CLINICAL MANIFESTATIONS Anaerobic Infections of the Mouth, Head, and Neck Anaerobic bacteria are commonly involved in infections of the mouth, head, and neck (Chap. 44). The predominant isolates are components of the normal microbiota of the upper airways—mainly the Bacteroides oralis group, pigmented Prevotella species, P. asaccharolytica, Fusobacterium species, peptostreptococci, and microaerophilic streptococci.


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InternalMed_Harrison. Soft tissue infections of the oral-facial area may or may not be odontogenic. Odontogenic infections—primarily dental caries and periodontal disease (gingivitis and periodontitis)—are common and have both local consequences (especially tooth loss) and the potential for life-threatening spread to the deep fascial spaces of the head and neck. Infections of the mouth can arise from either supragingival or subgingival dental plaque composed of bacteria colonizing the tooth surface. Supragingival plaque formation begins with the adherence of gram-positive bacteria to the tooth surface. This form of plaque is influenced by salivary and dietary components, oral hygiene, and local host factors. Supragingival plaque can lead to dental caries and, with further invasion, to pulpitis (endodontic infection) that can further perforate the alveolar bone, causing periapical abscess. Subgingival plaque is associated with periodontal infections (e.g., gingivitis, periodontitis, and periodontal abscess)


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InternalMed_Harrison. that can further perforate the alveolar bone, causing periapical abscess. Subgingival plaque is associated with periodontal infections (e.g., gingivitis, periodontitis, and periodontal abscess) that can further disseminate to adjacent structures such as the mandible, causing osteomyelitis of the maxillary sinuses. Periodontitis may also result in spreading infection that can involve adjacent bone or soft tissues. In the healthy periodontium, the sparse microbiota consists mainly of gram-positive organisms such as Streptococcus sanguinis and Actinomyces species. In the presence of gingivitis, there is a shift to a greater proportion of anaerobic gram-negative bacilli in the subgingival microbiota, with predominance of Prevotella intermedia. In well-established periodontitis, the complexity of the microbiota increases further. The predominant isolates are


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InternalMed_Harrison. P. gingivalis, P. intermedia, Aggregatibacter actinomycetemcomitans, Treponema denticola, and Tannerella forsythensis. Necrotizing ulcerative Gingivitis Gingivitis may become a necrotizing infection (trench mouth, Vincent’s stomatitis) (Chap. 44). The onset of disease is usually sudden and is associated with tender bleeding gums, foul breath, and a bad taste. The gingival mucosa, especially the 1097 papillae between the teeth, becomes ulcerated and may be covered by a gray exudate, which is removable with gentle pressure. Patients may become systemically ill, developing fever, cervical lymphadenopathy, and leukocytosis.


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InternalMed_Harrison. Noma (cancrum oris) is a necrotizing infection of the oral mucous membranes. It is characterized by destruction of soft tissue and bone and evolves rapidly from gingival inflammation to orofacial gangrene. Noma occurs most frequently in young children (1–4 years of age) with malnutrition or systemic disease. This infection occurs worldwide but is most common in sub-Saharan Africa.


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InternalMed_Harrison. Acute Necrotizing Infections of the Pharynx These infections usually occur in association with ulcerative gingivitis. Symptoms include an extremely sore throat, foul breath, and a bad taste accompanied by fever and a sensation of choking. Examination of the pharynx demonstrates that the tonsillar pillars are swollen, red, ulcerated, and covered with a grayish membrane that peels easily. Lymphadenopathy and leukocytosis are common. The disease may last for only a few days or, if not treated, may persist for weeks. Lesions begin unilaterally but may spread to the other side of the pharynx or the larynx. Aspiration of the infected material by the patient can result in lung abscesses. Peripharyngeal Space Infections These infections arise from the spread of organisms from the upper airways to potential spaces formed by the fascial planes of the head and neck. The etiology is typically polymicrobial and represents the normal microbiota of the mucosa of the originating site.


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InternalMed_Harrison. Peritonsillar abscess (quinsy) is a complication of acute tonsillitis caused mainly by a mixed flora containing anaerobes (e.g., F. necrophorum and Peptostreptococcus species) and the facultative anaerobe group A Streptococcus (Chap. 44). Of cases of submandibular space infection (Ludwig’s angina), 80% are caused by infection of the tissues surrounding the second and third molar teeth. This infection results in marked local swelling of tissues, with pain, trismus, and superior and posterior displacement of the tongue. Submandibular swelling of the neck can impair swallowing and cause respiratory obstruction. In some cases, tracheotomy is life-saving. Cervicofacial actinomycosis (Chap. 200) is caused by a branching, gram-positive, non-sporeforming, strict/facultative anaerobe that is a part of the normal oral microbiota. This chronic disease is characterized by abscesses, draining sinus tracts, fistula, bone destruction, and fibrosis. It can easily be mistaken for malignancy or


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InternalMed_Harrison. a part of the normal oral microbiota. This chronic disease is characterized by abscesses, draining sinus tracts, fistula, bone destruction, and fibrosis. It can easily be mistaken for malignancy or granulomatous disease. Actinomycosis less frequently involves the thorax, abdomen, pelvis, and CNS.


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InternalMed_Harrison. Sinusitis and Otitis Anaerobic bacteria have been implicated in chronic sinusitis but play little role in acute sinusitis. In several studies on chronic sinusitis, anaerobic bacteria were found in 0–52% of cases, depending on the method used to collect specimens. Polymicrobial infection is common, and the predominant anaerobic isolates are pigmented Prevotella, Fusobacterium, Peptostreptococcus, and P. acnes. Aerobic gram-negative bacilli and S. aureus have also been implicated in chronic sinusitis. Anaerobic bacteria have been isolated in a large percentage of cases of chronic suppurative otitis media in children. The role of anaerobes in acute otitis media is less clear.


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InternalMed_Harrison. Complications of Anaerobic Head and Neck Infections Contiguous cranial spread of these infections can result in osteomyelitis of the skull or mandible or in intracranial infections such as brain abscess and subdural empyema. Caudal spread can produce mediastinitis or pleuropulmonary infection. Hematogenous complications can also result from anaerobic infections of the head and neck. Bacteremia, which occasionally is polymicrobial, can lead to endocarditis or other distant infections. Lemierre’s syndrome (Chap. 44), which has been uncommon in the antimicrobial era, is an acute oropharyngeal infection with secondary septic thrombophlebitis of the internal jugular vein and frequent metastasis, most commonly to the lung. F. necrophorum is the usual cause. This infection typically begins with pharyngitis, which is followed by local invasion in the lateral pharyngeal space, with resultant internal jugular vein thrombophlebitis. A typical clinical


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InternalMed_Harrison. Infections Due to Mixed Anaerobic Organisms 1098 triad includes pharyngitis, a tender/swollen neck, and noncavitating pulmonary infiltrates. CNS Infections CNS infections associated with anaerobic bacteria are brain abscess, epidural abscess, and subdural empyema. Anaerobic meningitis is rare and is usually related to parameningeal collection or shunt infection. If optimal bacteriologic techniques are used, as many as 85% of brain abscesses yield anaerobic bacteria. Most anaerobic brain abscesses arise by direct extension from a site of otorhinolaryngeal infection such as otitis, sinusitis, or tooth infection. Hematogenous dissemination from a distant infected site, usually intraabdominal or pelvic, can occur. Common isolates are Peptostreptococcus, Fusobacterium, Bacteroides, Prevotella, Propionibacterium, Eubacterium, Veillonella, and Actinomyces species. Facultative or microaerophilic streptococci and coliforms are often part of a mixed infecting flora in brain abscesses.


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InternalMed_Harrison. Pleuropulmonary Infections Anaerobic pleuropulmonary infections result from the aspiration of oropharyngeal contents by patients with predisposing conditions such as dysphagia due to neurologic or esophageal disorders or transiently impaired consciousness due to conditions such as alcohol or drug abuse, seizures, head trauma, and cerebrovascular accidents. Clinical syndromes that are associated with anaerobic pleuropulmonary infection produced by aspiration include aspiration pneumonitis, which can be complicated by necrotizing pneumonia, lung abscess, and empyema. Many of these infections have an indolent course that may serve as a clinical clue differentiating them, for example, from pneumococcal pneumonia, which often presents with abrupt onset, shaking chills, and rapid progression.


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InternalMed_Harrison. The anaerobes most common in pleuropulmonary infections are indigenous to the oral cavity, especially the gingival crevice, and include pigmented and nonpigmented Prevotella, Peptostreptococcus, and Bacteroides species and F. nucleatum. Many of these infections are of mixed aerobic-anaerobic etiology, and the predominant aerobes isolated from community-acquired aspiration pneumonias are microaerophilic streptococci such as Streptococcus milleri. Studies using in-depth culture techniques in patients with community-acquired lung abscess showed aerobic and microaerophilic streptococci to be the most common pathogens (60% of patients) and anaerobes to be the second most common (26%). In a study on aspiration pneumonia from a long-term care facility, the most common isolates were gram-negative bacilli (49%), anaerobes (16%), and S. aureus (12%). Nosocomial aspiration pneumonia commonly involves a mixture of anaerobes and gram-negative bacilli or S. aureus.


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InternalMed_Harrison. aspiration pneUmonitis Bacterial aspiration pneumonitis must be distinguished from two other clinical syndromes associated with aspiration that are not of bacterial etiology. One syndrome results from aspiration of solids, usually food. Obstruction of major airways typically results in atelectasis and moderate nonspecific inflammation. Therapy consists of removal of the foreign body. The second aspiration syndrome is more easily confused with bacterial aspiration. Mendelson’s syndrome, a chemical pneumonitis, results from regurgitation of stomach contents and aspiration of chemical material, usually acidic gastric juices. Pulmonary inflammation—including the destruction of the alveolar lining, with transudation of fluid into the alveolar space—occurs with remarkable rapidity. Typically this syndrome develops within hours, often following anesthesia when the gag reflex is depressed. The patient becomes tachypneic, hypoxic, and febrile. The leukocyte count may rise, and the chest x-ray


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InternalMed_Harrison. syndrome develops within hours, often following anesthesia when the gag reflex is depressed. The patient becomes tachypneic, hypoxic, and febrile. The leukocyte count may rise, and the chest x-ray may evolve from normal to a complete bilateral “whiteout” within 8–24 h. Sputum production is minimal. The pulmonary signs and symptoms can resolve quickly with symptom-based therapy or can culminate in respiratory failure, with the subsequent development of bacterial superinfection over a period of days. Antibiotic therapy is not indicated unless bacterial infection supervenes.


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InternalMed_Harrison. In contrast to these syndromes, bacterial aspiration pneumonitis develops over a period of several days or weeks rather than hours. Patients who enter the hospital with this syndrome typically have been ill for several days and generally report low-grade fever, malaise, and sputum production. In some patients, weight loss and anemia reflect a more chronic process. Usually the history reveals factors predisposing to aspiration, such as alcohol overdose or residence in a nursing home. Examination sometimes yields evidence of periodontal disease. Sputum characteristically is not malodorous unless the process has been under way for at least a week. A mixed bacterial flora with many PMNs is evident on Gram’s staining of sputum. Expectorated sputum is unreliable for anaerobic cultures because of inevitable contamination by the normal oral microbiota. Reliable specimens for culture can be obtained by transtracheal or transthoracic aspiration—techniques that are rarely used at present.


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InternalMed_Harrison. of inevitable contamination by the normal oral microbiota. Reliable specimens for culture can be obtained by transtracheal or transthoracic aspiration—techniques that are rarely used at present. Culture of protected-brush specimens or bronchoalveolar lavage fluid obtained by bronchoscopy is controversial.


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InternalMed_Harrison. Chest x-rays show consolidation in dependent pulmonary segments: in the basilar segments of the lower lobes if the patient has aspirated while upright and in either the posterior segment of the upper lobe (usually on the right side) or the superior segment of the lower lobe if the patient has aspirated while supine. necrotizing pneUmonitis This form of anaerobic pneumonitis is characterized by numerous small abscesses that spread to involve several pulmonary segments. The process can be indolent or fulminating. This syndrome is less common than either aspiration pneumonitis or lung abscess and includes features of both types of infection.


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InternalMed_Harrison. anaerobic lUng abscesses (See also Chap. 154) These abscesses result from subacute anaerobic pulmonary infection. The clinical syndrome typically involves a history of constitutional signs and symptoms (including malaise, weight loss, fever, night sweats, and foul-smelling sputum), perhaps over a period of weeks (Chap. 153). Patients who develop lung abscesses characteristically have dental infection and periodontitis, but lung abscesses in edentulous patients have been reported. Abscess cavities may be single or multiple and generally occur in dependent pulmonary segments (Fig. 201-1). Anaerobic abscesses must be distinguished from lesions associated with tuberculosis, neoplasia, and other conditions. Septic pulmonary emboli may originate from intraabdominal or female genital tract infections and can produce anaerobic pneumonia and abscess.


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InternalMed_Harrison. Septic pulmonary emboli may originate from intraabdominal or female genital tract infections and can produce anaerobic pneumonia and abscess. empyema Empyema is a manifestation of long-standing anaerobic pulmonary infection complicated by bronchopleural fistula. The clinical presentation, which includes foul-smelling sputum, resembles that FIGuRE 201-1 Chest radiograph of right-lower-lobe lung abscess in a 60-year-old alcoholic patient. (From GL Mandell [ed]: Atlas of Infectious Diseases, Vol VI. Philadelphia, Current Medicine Inc, Churchill Livingstone, 1996; with permission.) of other anaerobic pulmonary infections. Patients may report pleuritic chest pain and marked chest-wall tenderness.


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InternalMed_Harrison. Empyema may be masked by overlying pneumonitis and should be considered especially in cases of persistent fever despite antibiotic therapy. Diligent physical examination and the use of ultrasound to localize a loculated empyema are important diagnostic tools. The collection of a foul-smelling exudate by thoracentesis is typical. Cultures of infected pleural fluid yield an average of 3.5 anaerobic and 0.6 facultative or aerobic bacterial species. Drainage is required. Defervescence, a return to a feeling of well-being, and resolution of the process may require several months. Extension from a subdiaphragmatic infection may also result in anaerobic empyema.


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InternalMed_Harrison. Intraabdominal Infections Intraabdominal infections—mainly peritonitis and abscesses—are usually polymicrobial and represent the normal intestinal (especially colonic) microbiota. These infections most often follow a breach in the mucosal barrier resulting from appendicitis, diverticulitis, neoplasm, inflammatory bowel disease, surgery, or trauma. On average, four to six bacterial species are isolated per specimen submitted to the microbiology laboratory, with a predominance of enteric aerobic/facultative gram-negative bacilli, anaerobes, and streptococci/enterococci. The most common isolates are Escherichia coli (found in ≥50% of patients) and B. fragilis (30– 50%). Other anaerobes commonly isolated from this type of infection include Peptostreptococcus, Prevotella, and Fusobacterium species. The involvement of clostridia can lead to severe infections. The dominance of four to six bacterial species out of the more than 500 colonic mucosal species is related both to the virulence


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InternalMed_Harrison. species. The involvement of clostridia can lead to severe infections. The dominance of four to six bacterial species out of the more than 500 colonic mucosal species is related both to the virulence factors of these species and to the inability of clinical laboratories to culture many other species residing in the colonic mucosa.


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InternalMed_Harrison. Disease originating from proximal-bowel perforation reflects the microbiota of this site, with a predominance of aerobic and anaerobic gram-positive bacteria and Candida. Neutropenic enterocolitis (typhlitis) has been associated with anaerobic infection of the cecum but—in the setting of neutropenia (Chap. 104)—may involve the entire bowel. Patients usually present with fever; abdominal pain, tenderness, and distention; and watery diarrhea. The bowel wall is edematous with hemorrhage and necrosis. The primary pathogen is thought by some authorities to be Clostridium septicum, but other clostridia and mixed anaerobes have also been implicated. More than 50% of patients developing early clinical signs can benefit from antibiotic therapy and bowel rest. Surgery is sometimes required to remove gangrenous bowel. See Chap. 159 for a complete discussion of intraabdominal infections.


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InternalMed_Harrison. Enterotoxigenic B. fragilis has been associated with watery diarrhea in a few young children and adults. In case–control studies of children with undiagnosed diarrheal disease, enterotoxigenic B. fragilis was isolated from significantly more children with diarrhea than children in the control group.


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InternalMed_Harrison. Pelvic Infections The vagina of a healthy woman is a major reservoir of anaerobic and aerobic bacteria. In the normal microbiota of the female genital tract, anaerobes outnumber aerobes by a ratio of ~10:1 and include anaerobic gram-positive cocci and Bacteroides species (Table 201-1). Anaerobes are isolated from most women with genital tract infections that are not caused by a sexually transmitted pathogen. The major anaerobic pathogens are B. fragilis, P. bivia, P. disiens, P. melaninogenica, anaerobic cocci, and Clostridium species. Anaerobes are frequently encountered in pelvic inflammatory disease, pelvic abscess, endometritis, tubo-ovarian abscess, septic abortion, and postoperative or postpartum infections. These infections are often of mixed etiology, involving both anaerobes and coliforms; pure anaerobic infections without coliform or other facultative bacterial species occur more often in pelvic than in intraabdominal sites. Septic pelvic thrombophlebitis may complicate the


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InternalMed_Harrison. coliforms; pure anaerobic infections without coliform or other facultative bacterial species occur more often in pelvic than in intraabdominal sites. Septic pelvic thrombophlebitis may complicate the infections and lead to repeated episodes of septic pulmonary emboli. See Chap. 163 for a complete discussion of pelvic inflammatory disease.


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InternalMed_Harrison. Anaerobic bacteria have been thought to be contributing factors in the etiology of bacterial vaginosis. This syndrome of unknown etiology is characterized by a profuse malodorous discharge and a change in the bacterial ecology that results in replacement of the Lactobacillus-1099 dominated normal microbiota with an overgrowth of bacterial species including Gardnerella vaginalis, Prevotella species, Mobiluncus species, peptostreptococci, and genital mycoplasmas. A study based on 16S rRNA identification found other anaerobes that were predominant in cases but not in controls: Atopobium, Leptotrichia, Megasphaera, and Eggerthella. Pelvic infections due to Actinomyces species have been associated with the use of intrauterine devices (Chap. 200).


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InternalMed_Harrison. Skin and Soft Tissue Infections Injury to skin, bone, or soft tissue by trauma, ischemia, or surgery creates a suitable environment for anaerobic infections. These infections are most frequently found in sites prone to contamination with feces or with upper airway secretions— e.g., wounds associated with intestinal surgery, decubitus ulcers, or human bites. Moreover, anaerobes have been isolated from cutaneous abscesses, rectal abscesses, and axillary sweat gland infections (hidradenitis suppurativa). Anaerobes also are often cultured from foot ulcers of diabetic patients. The deep soft-tissue infections associated with anaerobic bacteria are crepitant cellulitis, synergistic cellulitis, gangrene, and necrotizing fasciitis (Chaps. 156 and 179).


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InternalMed_Harrison. These soft tissue or skin infections are usually polymicrobial. A mean of 4.8 bacterial species are isolated, with an anaerobe-toaerobe ratio of ~3:2. The most frequently isolated organisms include Bacteroides, Peptostreptococcus, Clostridium, Enterococcus, and Proteus species. The involvement of anaerobes in these types of infections is associated with a higher frequency of fever, foul-smelling lesions, gas in the tissues, and visible foot ulcer.


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InternalMed_Harrison. Anaerobic bacterial synergistic gangrene (Meleney’s gangrene), a rare infection of the superficial fascia, is characterized by exquisite pain, redness, and swelling followed by induration. Erythema surrounds a central zone of necrosis. A granulating ulcer forms at the original center as necrosis and erythema extend outward. Symptoms are limited to pain; fever is not typical. These infections usually involve a combination of Peptostreptococcus species and S. aureus; the usual site of infection is an abdominal surgical wound or the area surrounding an ulcer on an extremity. Treatment includes surgical removal of necrotic tissue and antimicrobial administration.


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InternalMed_Harrison. Necrotizing fasciitis, a rapidly spreading destructive disease of the fascia, is usually attributed to group A streptococci (Chap. 173) but can also be a mixed infection involving anaerobes and aerobes, usually occurring after surgeries and in patients with diabetes or peripheral vascular disease. The most frequently isolated anaerobes in these infections are Peptostreptococcus and Bacteroides species. Gas may be found in the tissues. Similarly, myonecrosis can be associated with mixed anaerobic infection. Fournier’s gangrene consists of cellulitis involving the scrotum, perineum, and anterior abdominal wall, with mixed anaerobic organisms spreading along deep external fascial planes and causing extensive loss of skin.


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InternalMed_Harrison. Bone and Joint Infections Although actinomycosis (Chap. 200) accounts on a worldwide basis for most anaerobic infections in bone, organisms including peptostreptococci or microaerophilic cocci, Bacteroides species, Fusobacterium species, and Clostridium species can also be involved in osteomyelitis (Chap. 158). These infections frequently arise adjacent to soft tissue infections. Many patients with osteomyelitis due to anaerobic bacteria have evidence of an anaerobic infection elsewhere in the body; most commonly, infected adjacent soft-tissue sites are the source of the organisms involved. Examples are diabetic foot ulcers and decubitus ulcers that may be complicated by mixed aerobic-anaerobic osteomyelitis. Hematogenous seeding of bone is uncommon. Prevotella and Porphyromonas species are detected in infections involving the maxilla and mandible, whereas Clostridium species have been reported as anaerobic pathogens in cases of osteomyelitis of the long bones following fracture or


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InternalMed_Harrison. are detected in infections involving the maxilla and mandible, whereas Clostridium species have been reported as anaerobic pathogens in cases of osteomyelitis of the long bones following fracture or trauma. Fusobacteria have been isolated in pure culture from sites of osteomyelitis adjacent to the perinasal sinuses. Peptostreptococci and microaerophilic cocci have been reported as significant pathogens in infections involving the skull, mastoid, and prosthetic implants placed in bone. In patients with osteomyelitis, the most reliable culture specimen is a bone biopsy sample free of normal uninfected skin and subcutaneous tissue.


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InternalMed_Harrison. Infections Due to Mixed Anaerobic Organisms 1100 In contrast to anaerobic osteomyelitis, most cases of anaerobic arthritis (Chap. 157) involve a single isolate, and most cases are secondary to hematogenous spread. The most common isolates are Fusobacterium species. Most of the patients involved have uncontrolled peritonsillar infections progressing to septic cervical venous thrombophlebitis (Lemierre’s syndrome) and resulting in hematogenous dissemination with a predilection for the joints. Unlike anaerobic osteomyelitis, anaerobic pyoarthritis in most cases is not polymicrobial and may be acquired hematogenously. Anaerobes are important pathogens in infections involving prosthetic joints; in these infections, the causative organisms (such as Peptostreptococcus species and P. acnes) are part of the normal skin microbiota.


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InternalMed_Harrison. Bacteremia Transient bacteremia is a well-known event in healthy individuals whose anatomic mucosal barriers have been injured (e.g., during dental extractions or dental scaling). These bacteremic episodes, which are often due to anaerobes, have no pathologic consequences. However, anaerobic bacteria are found in cultures of blood from clinically ill patients when proper culture techniques are used. Anaerobes have accounted for 5% (range at various institutions, 0.5–12%) of cases of clinically significant bacteremia. The incidence of anaerobic bacteremia decreased from the 1970s through the early 1990s. This change may have been related to the administration of antibiotic prophylaxis before intestinal surgery, the earlier recognition of localized infections, and the empirical use of broad-spectrum antibiotics for presumed infection. Recent reports present conflicting data regarding rates of anaerobic bacteremia. A study from the Mayo Clinic compared three periods (1993–1996,


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InternalMed_Harrison. of broad-spectrum antibiotics for presumed infection. Recent reports present conflicting data regarding rates of anaerobic bacteremia. A study from the Mayo Clinic compared three periods (1993–1996, 1997–2000, and 2001–2004) and found a 74% increase in the mean incidence of anaerobic bacteremia; this finding contrasts with a 45% decrease in incidence from 1977 to 1988 at the same institution. In contrast, a report from Switzerland compared two periods (1997–2001 and 2002–2006) and found decreases in both the number of anaerobe-positive blood cultures and the proportion of all blood culture isolates that were anaerobes.


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InternalMed_Harrison. The majority of anaerobic bacteremias are due to gram-negative bacilli—mainly the B. fragilis group, with B. fragilis most commonly isolated (60–80% of cases). Other organisms causing bacteremia include Clostridium species (10%), Peptostreptococcus species (10%), and Fusobacterium species (5%).


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InternalMed_Harrison. Once the organism in the blood has been identified, both the portal of bloodstream entry and the underlying problem that probably led to seeding of the bloodstream can often be deduced from an understanding of the organism’s normal site of residence. For example, mixed anaerobic bacteremia including B. fragilis usually implies a colonic pathology with mucosal disruption from neoplasia, diverticulitis, or some other inflammatory lesion. Debilitating diseases such as malignancies, diabetes, organ transplantation, and abdominal and pelvic surgeries are among the predisposing factors for anaerobic bacteremia. In a retrospective nested case–control study, diabetes was identified as a risk factor for anaerobic bacteremia when the source of bacteremia was unknown. The initial manifestations are determined by the portal of entry and reflect the localized condition. When bloodstream invasion occurs, patients can become extremely ill, with rigors and hectic fevers. The clinical picture may be


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InternalMed_Harrison. determined by the portal of entry and reflect the localized condition. When bloodstream invasion occurs, patients can become extremely ill, with rigors and hectic fevers. The clinical picture may be quite similar to that seen in sepsis involving aerobic gram-negative bacilli. Although complications of anaerobic bacteremia (e.g., septic thrombophlebitis and septic shock) have been reported, their incidence in association with anaerobic bacteremia is low. Anaerobic bacteremia is potentially fatal and requires rapid diagnosis and appropriate therapy. Reported case–fatality rates are high, ranging from 25% to 44%, and appear to increase with the age of the patient (with reported rates of >66% among patients >60 years old), with the isolation of multiple species from the bloodstream, and with the failure to surgically remove a focus of infection. The attributable mortality rate for bacteremia associated with the B. fragilis group was examined in a matched case–control study. Patients with


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InternalMed_Harrison. the failure to surgically remove a focus of infection. The attributable mortality rate for bacteremia associated with the B. fragilis group was examined in a matched case–control study. Patients with B. fragilis–group bacteremia had a significantly higher mortality rate (28% vs 8%), with an attributable mortality rate of 19.3% and a mortality risk ratio of 3.2.


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InternalMed_Harrison. Endocarditis and Pericarditis (See also Chap. 155) Endocarditis due to anaerobes is uncommon. However, anaerobic streptococci, which are often classified incorrectly, are responsible for this disease more frequently than is generally appreciated. Gram-negative anaerobes are unusual causes of endocarditis. Signs and symptoms of anaerobic endocarditis are similar to those of endocarditis due to facultative organisms. Mortality rates of 21–43% have been reported for anaerobic endocarditis. Anaerobes, particularly B. fragilis and Peptostreptococcus species, are uncommonly found in infected pericardial fluids. Anaerobic pericarditis is associated with a mortality rate of >50%. Anaerobes can reach the pericardial space by hematogenous spread, by spread from a contiguous site of infection (e.g., heart or esophagus), or by direct inoculation arising from trauma or surgery.


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InternalMed_Harrison. There are three critical steps in the diagnosis of anaerobic infection: (1) proper collection of specimens; (2) rapid transport of the specimens to the microbiology laboratory, preferably in anaerobic transport media; and (3) proper handling of the specimens by the laboratory. Specimens must be collected by meticulous sampling of infected sites, with avoidance of contamination by the normal microbiota. When such contamination is likely, the specimen is unacceptable. Examples of specimens unacceptable for anaerobic culture include sputum collected by expectoration or nasal tracheal suction, bronchoscopy specimens, samples collected directly through the vaginal vault, urine collected by voiding, and feces. Specimens appropriate for anaerobic culture include sterile body fluids such as blood, pleural fluid, peritoneal fluid, cerebrospinal fluid, and aspirates or biopsy samples from normally sterile sites. As a general rule, liquid or tissue specimens are preferred; swab specimens should


InternalMed_Harrison

InternalMed_Harrison. pleural fluid, peritoneal fluid, cerebrospinal fluid, and aspirates or biopsy samples from normally sterile sites. As a general rule, liquid or tissue specimens are preferred; swab specimens should be avoided.


InternalMed_Harrison

InternalMed_Harrison. Because even brief exposure to oxygen may kill some anaerobic organisms and result in failure to isolate them in the laboratory, air must be expelled from the syringe used to aspirate the abscess cavity, and the needle must be capped with a sterile rubber stopper. It is also important to remember that prior antibiotic therapy reduces the cultivability of these bacteria. Specimens can be injected into transport bottles containing a reduced medium or taken immediately in syringes to the laboratory for direct culture on anaerobic media. Delays in transport may lead to a failure to isolate anaerobes due to exposure to oxygen or overgrowth of facultative organisms, which may eliminate or obscure any anaerobes that are present. All clinical specimens from suspected anaerobic infections should be subjected to Gram’s staining and examined for organisms with characteristic morphology. It is not unusual for organisms to be observed on Gram’s staining but not isolated in culture.


InternalMed_Harrison

InternalMed_Harrison. Because of the time and difficulty involved in the isolation of anaerobic bacteria, diagnosis of anaerobic infections must frequently be based on presumptive evidence. There are few clinical clues to the probable presence of anaerobic bacteria at infected sites. The involvement of certain sites with lowered oxidation-reduction potential (e.g., avascular necrotic tissues) and the presence of an abscess favor the diagnosis of an anaerobic infection. When infections occur in proximity to mucosal surfaces normally harboring an anaerobic microbiota, such as the gastrointestinal tract, female genital tract, or oropharynx, anaerobes should be considered as potential etiologic agents. A foul odor is often indicative of anaerobes, which produce certain organic acids as they proliferate in necrotic tissue. Although these odors are nearly pathognomonic for anaerobic infection, the absence of odor does not exclude an anaerobic etiology. The presence of gas in tissues is highly suggestive, but not


InternalMed_Harrison

InternalMed_Harrison. tissue. Although these odors are nearly pathognomonic for anaerobic infection, the absence of odor does not exclude an anaerobic etiology. The presence of gas in tissues is highly suggestive, but not diagnostic, of anaerobic infection. Because anaerobes often coexist with other bacteria and cause mixed or synergistic infection, Gram’s staining of exudate frequently reveals multiple morphotypes suggestive of anaerobes. Sometimes these organisms have morphologic characteristics associated with specific species.


InternalMed_Harrison

InternalMed_Harrison. When cultures of obviously infected sites or purulent material yield no growth, streptococci only, or a single aerobic species (such as E. coli) and Gram’s staining reveals a mixed flora, the involvement of anaerobes should be suspected; the implication is that the anaerobic microorganisms have failed to grow because of inadequate transport and/ or culture techniques. Failure of an infection to respond to antibiotics that are not active against anaerobes (e.g., aminoglycosides and—in some circumstances—penicillin, cephalosporins, or tetracyclines) suggests an anaerobic etiology.


InternalMed_Harrison

InternalMed_Harrison. Successful therapy for anaerobic infections requires the administration of a combination of appropriate antibiotics, surgical resection, debridement of devitalized tissues, and drainage either surgically or percutaneously (guided by an imaging technique such as CT , MRI, or ultrasound). Any anatomic breach must be closed promptly, closed spaces drained, tissue compartments decompressed, and an adequate blood supply established. Abscess cavities should be drained as soon as fluctuation or localization occurs.


InternalMed_Harrison

InternalMed_Harrison. The antibiotics used to treat anaerobic infections should be active against both aerobic and anaerobic organisms because many of these infections are of mixed etiology. Antibiotic regimens can usually be selected empirically on the basis of the type of infection, the species of the organisms usually present in such cases, the results of Gram’s staining, and a knowledge of antimicrobial resistance patterns (Chap. 170 and Table 201-2). Other factors influencing the selection of antibiotics include need for bactericidal activity and for penetration into certain organs (such as the brain), toxicity, and impact on the normal microbiota. Antibiotics active against clinically relevant anaerobes can be grouped into four categories based on their predicted activity (Table 201-2). Nearly all the drugs listed have toxic side effects, which are described in detail in Chap. 170.


InternalMed_Harrison

InternalMed_Harrison. Antibiotic susceptibility testing of anaerobic bacteria has been difficult and controversial. Because of the slow growth rate of many anaerobes, the lack of standardized testing methods and of clinically relevant standards for resistance, and the generally good results obtained with empirical therapy, there has been limited interest in testing these organisms for antibiotic susceptibility. However, one study of antibiotic-treated patients with Bacteroides isolates from blood found mortality rates of 45% among those whose isolates were deemed resistant to the agent used and 16% among those whose isolates were deemed sensitive. It is accepted that testing is important for patients with serious or prolonged infections or in cases in which antibiotics have not had an impact. Testing is also helpful in monitoring the activity of new drugs and recording current resistance patterns among anaerobic pathogens. The antibiotics with the greatest activity against nearly all anaerobic bacteria


InternalMed_Harrison

InternalMed_Harrison. helpful in monitoring the activity of new drugs and recording current resistance patterns among anaerobic pathogens. The antibiotics with the greatest activity against nearly all anaerobic bacteria include carbapenems, β-lactam/β-lactamase inhibitor combinations, metronidazole, and chloramphenicol.


InternalMed_Harrison

InternalMed_Harrison. Antibiotic resistance in anaerobic bacteria is an increasing problem. Resistance rates vary with the institution and the geographic region. In recent years, the activity of clindamycin, cefoxitin, cefotetan, and moxifloxacin has decreased against B. fragilis and related strains (B. distasonis, B. ovatus, B. thetaiotaomicron, B. uniformis, B. vulgatus). Multidrug-resistant B. fragilis has recently been reported. Nearly all organisms in the B. fragilis group (>97%) are 1101 resistant to penicillin G. The cephamycins cefoxitin and cefotetan display greater activity against this group, but rates of resistance have increased, with current figures at ~10% in the United States and higher in Argentina (28%) and Europe (17%). Rates of resistance to β-lactam agents among anaerobes other than Bacteroides are lower but are highly variable. β-Lactam/β-lactamase inhibitor combinations such as ampicillin/sulbactam, ticarcillin/clavulanic acid, and piperacillin/tazobactam are usually good therapeutic


InternalMed_Harrison

InternalMed_Harrison. are lower but are highly variable. β-Lactam/β-lactamase inhibitor combinations such as ampicillin/sulbactam, ticarcillin/clavulanic acid, and piperacillin/tazobactam are usually good therapeutic options against β-lactamase-producing anaerobes, including the B. fragilis group. Although resistance rates reported from most countries are still low, several studies have documented nonsusceptibility to ampicillin/sulbactam in 0.5–3% of isolates in the United States, 3–10% in Europe, and 1–8% in Argentina. Recently, up to 48% of B. fragilis isolates in Taiwan were found to be nonsusceptible to ampicillin/sulbactam, and a significant increase in resistance to this combination was also identified among other Bacteroides, Prevotella, and Fusobacterium species.


InternalMed_Harrison

InternalMed_Harrison. Carbapenems (ertapenem, doripenem, meropenem, and imipenem) are equally active against anaerobes, with <1% of B. fragilis strains showing resistance in the United States and Europe. Higher rates of carbapenem nonsusceptibility are being reported from some countries (5% in Germany, 8% [to doripenem] in Canada, and 7–12% in Taiwan).


InternalMed_Harrison

InternalMed_Harrison. Metronidazole is active against gram-negative anaerobes, including the B. fragilis group; resistance, although rare (<1%), has been reported in both Europe and the United States. Resistance to metronidazole is more common among gram-positive anaerobes, including P. acnes, Actinomyces species, lactobacilli, and anaerobic streptococci. Clindamycin is active against many anaerobes. However, rates of resistance to clindamycin among the B. fragilis group have increased in the United States from 3% in 1982 to 16% in 1996 and 26% in 2000, with rates as high as 40–50% in some series. Resistance to clindamycin among non-Bacteroides anaerobes is much less common (<10%). Tigecycline is active against some anaerobic bacteria, including


InternalMed_Harrison

InternalMed_Harrison. Tigecycline is active against some anaerobic bacteria, including Peptostreptococcus, Propionibacterium, Prevotella, Fusobacterium, and most Bacteroides species. Its efficacy for treatment of intraabdominal infections was comparable to that of imipenem in two phase 3 double-blind clinical trials. This drug is therefore recommended as single-agent treatment for complicated intraabdominal infections, but resistance (~6%) among Bacteroides and non-Bacteroides species has been reported.


InternalMed_Harrison

InternalMed_Harrison. Fluoroquinolones such as moxifloxacin have shown potential in the treatment of mixed aerobic-anaerobic infections. A survey in the United States found a 38% rate of resistance to moxifloxacin among the B. fragilis group; in Europe 14–30% of isolates were nonsusceptible to this drug, as were 7–25% of anaerobes isolated from blood cultures in Taiwan. Despite excellent in vitro activity against all clinically important anaerobes, chloramphenicol is less desirable than other active drugs for the treatment of anaerobic infection because of documented clinical failures.


InternalMed_Harrison

InternalMed_Harrison. Infections Due to Mixed Anaerobic Organisms aUsually needs to be given in combination with aerobic bacterial coverage. For infections originating below the diaphragm, aerobic gram-negative coverage is essential. For infections from an oral source, aerobic gram-positive coverage is added. Metronidazole also is not active against Actinomyces, Propionibacterium, or other gram-positive non-spore-forming bacilli (e.g., Eubacterium, Bifidobacterium) and is unreliable against peptostreptococci. bDespite excellent in vitro activity against all clinically important anaerobes, this drug is less desirable than other active drugs because of documented clinical failures. affected prehominids. This disease most often affects the lungs, although other organs are involved in up to one-third of cases. If properly treated, TB caused by drug-susceptible strains is curable in the vast majority of


InternalMed_Harrison

InternalMed_Harrison. TB caused by drug-susceptible strains is curable in the vast majority of Mario C. Raviglione cases. If untreated, the disease may be fatal within 5 years in 50–65% of cases. Transmission usually takes place through the airborne spread of droplet nuclei produced by patients with infectious pulmonary TB.


InternalMed_Harrison

InternalMed_Harrison. Tuberculosis (TB), which is caused by bacteria of the Mycobacterium tuberculosis complex, is one of the oldest diseases known to affect humans and a major cause of death worldwide. Recent population genomic studies suggest that M. tuberculosis may have emerged ~70,000 years ago in Mycobacteria belong to the family Mycobacteriaceae and the orderAfrica and subsequently disseminated along with anatomically modern Actinomycetales. Of the pathogenic species belonging to the M. tuber-humans, expanding globally during the Neolithic Age as human den-culosis complex, which comprises eight distinct subgroups, the mostsity started to increase. Progenitors of M. tuberculosis are likely to have common and important agent of human disease is M. tuberculosis. The complex includes M. bovis (the bovine tubercle bacillus—characteristically resistant to pyrazinamide, once an important cause of TB transmitted by unpasteurized milk, and currently the cause of a small percentage of human cases worldwide),


InternalMed_Harrison

InternalMed_Harrison. bacillus—characteristically resistant to pyrazinamide, once an important cause of TB transmitted by unpasteurized milk, and currently the cause of a small percentage of human cases worldwide), M. caprae (related to M. bovis), M. africanum (isolated from cases in West, Central, and East Africa), M. microti (the “vole” bacillus, a less virulent and rarely encountered organism), M. pinnipedii (a bacillus infecting seals and sea lions in the Southern Hemisphere and recently isolated from humans), M. mungi (isolated from banded mongooses in southern Africa), M. orygis (described recently in oryxes and other Bovidae in Africa and Asia and a potential cause of infection in humans), and M. canetti (a rare isolate from East African cases that produces unusual smooth colonies on solid media and is considered closely related to a supposed progenitor type).


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 202-1 Acid-fast bacillus smear showing M. tuberculosis bacilli. (Courtesy of the Centers for Disease Control and Prevention, Atlanta.) M. tuberculosis is a rod-shaped, non-spore-forming, thin aerobic bacterium measuring 0.5 μm by 3 μm. Mycobacteria, including


InternalMed_Harrison

InternalMed_Harrison. M. tuberculosis, are often neutral on Gram’s staining. However, once stained, the bacilli cannot be decolorized by acid alcohol; this characteristic justifies their classification as acid-fast bacilli (AFB; Fig. 202-1). Acid fastness is due mainly to the organisms’ high content of mycolic acids, long-chain cross-linked fatty acids, and other cell-wall lipids. Microorganisms other than mycobacteria that display some acid fastness include species of Nocardia and Rhodococcus, Legionella micdadei, and the protozoa Isospora and Cryptosporidium. In the mycobacterial cell wall, lipids (e.g., mycolic acids) are linked to underlying arabinogalactan and peptidoglycan. This structure results in very low permeability of the cell wall, thus reducing the effectiveness of most antibiotics. Another molecule in the mycobacterial cell wall, lipoarabinomannan, is involved in the pathogen–host interaction and facilitates the survival of M. tuberculosis within macrophages. The complete genome sequence of


InternalMed_Harrison

InternalMed_Harrison. in the mycobacterial cell wall, lipoarabinomannan, is involved in the pathogen–host interaction and facilitates the survival of M. tuberculosis within macrophages. The complete genome sequence of M. tuberculosis comprises 4043 genes encoding 3993 proteins and 50 genes encoding RNAs; its high guanine-plus-cytosine content (65.6%) is indicative of an aerobic “lifestyle.” A large proportion of genes are devoted to the production of enzymes involved in cell wall metabolism.


InternalMed_Harrison

InternalMed_Harrison. More than 5.7 million new cases of TB (all forms, both pulmonary and extrapulmonary) were reported to the World Health Organization (WHO) in 2013; 95% of cases were reported from developing countries. However, because of insufficient case detection and incomplete notification, reported cases may represent only about two-thirds of the total estimated cases. The WHO estimated that 9 million (range, 8.6–9.4 million) new cases of TB occurred worldwide 1103 in 2013, 95% of them in developing countries of Asia (5 million), Africa (2.6 million), the Middle East (0.7 million), and Latin America (0.3 million). It is further estimated that 1.49 million (range, 1.32–1.67 million) deaths from TB, including 0.36 million among people living with HIV infection, occurred in 2013, 96% of them in developing countries. Estimates of TB incidence rates (per 100,000 population) and numbers of TB-related deaths in 2013 are depicted in Figs. 202-2 and 202-3, respectively. During the late 1980s and early


InternalMed_Harrison

InternalMed_Harrison. countries. Estimates of TB incidence rates (per 100,000 population) and numbers of TB-related deaths in 2013 are depicted in Figs. 202-2 and 202-3, respectively. During the late 1980s and early 1990s, numbers of reported cases of TB increased in industrialized countries. These increases were related largely to immigration from countries with a high incidence of TB; the spread of the HIV epidemic; social problems, such as increased urban poverty, homelessness, and drug abuse; and dismantling of TB services. During the past few years, numbers of reported cases have begun to decline again or have stabilized in most industrialized nations. In the United States, with the re-establishment of stronger control programs, the decline resumed in 1993 and has since been maintained. In 2013, 9582 cases of TB (3.0 cases/100,000 population) were reported to the Centers for Disease Control and Prevention (CDC).


InternalMed_Harrison

InternalMed_Harrison. In the United States, TB is uncommon among young adults of European descent, who have only rarely been exposed to M. tuberculosis infection during recent decades. In contrast, because of a high risk of transmission in the past, the prevalence of latent


InternalMed_Harrison

InternalMed_Harrison. M. tuberculosis infection (LTBI) is relatively high among elderly whites. In general, adults ≥65 years of age have the highest incidence rate per capita (4.9 cases/100,000 population in 2013) and children <14 years of age the lowest (0.8 case/100,000 population). Blacks account for the highest proportion of cases (37%; 1257 cases in 2013) among U.S.-born persons. TB in the United States is also a disease of adult members of the HIV-infected population, the foreign-born population (64.6% of all cases in 2013), and disadvantaged/marginalized populations. Of the 6193 cases reported among foreign-born persons in 2013, 37% occurred in persons from the Americas and 32% occurred in persons born in the Western Pacific region. Overall, the highest rates per capita were among Asian Americans (18.7 cases/100,000 population). A total of 536 deaths were caused by TB in the United States in 2011. In Canada in 2013, 1638 TB cases were reported (4.7 cases/100,000 population); 70% (1145) of these


InternalMed_Harrison

InternalMed_Harrison. cases/100,000 population). A total of 536 deaths were caused by TB in the United States in 2011. In Canada in 2013, 1638 TB cases were reported (4.7 cases/100,000 population); 70% (1145) of these cases occurred in foreign-born persons and 19% (309 cases) occurred in members of the Canadian aboriginal peoples, whose per capita rate is disproportionately high (23.4 cases/100,000 population) with a peak in the Nunavut territory of 143 cases/100,000 population—a rate similar to that in many highly endemic countries. Similarly, in Europe, TB has reemerged as an important public health problem, mainly as a result of cases among immigrants from high-incidence countries and among marginalized populations, often in large urban settings like London; in 2013, 41% of all cases reported from the United Kingdom occurred in London, and the rate per capita (36 cases/100,000 population) was similar to that in some middle-income countries. In most Western European countries, there are more cases


InternalMed_Harrison

InternalMed_Harrison. United Kingdom occurred in London, and the rate per capita (36 cases/100,000 population) was similar to that in some middle-income countries. In most Western European countries, there are more cases annually among foreign-born than native populations.


InternalMed_Harrison

InternalMed_Harrison. Recent data on global trends indicate that in 2013 the TB incidence was stable or falling in most regions; this trend began in the early 2000s and appears to have continued, with an average annual decline of 2% globally. This global decrease is explained largely by the simultaneous reduction in TB incidence in sub-Saharan Africa, where rates had risen steeply since the 1980s as a result of the HIV epidemic and the lack of capacity of health systems and services to deal with the problem effectively, and in Eastern Europe, where incidence increased rapidly during the 1990s because of a deterioration in socioeconomic conditions and the health care infrastructure (although, after peaking in 2001, incidence in Eastern Europe has since declined slowly).


InternalMed_Harrison

InternalMed_Harrison. Of the estimated 9 million new cases of TB in 2013, 13% (1.1 million) were associated with HIV infection, and 78% of these HIV-associated cases occurred in Africa. An estimated 0.36 million persons with HIV-associated TB died in 2013. Furthermore, an estimated 480,000 cases (range, 350,000–610,000) of multidrug-resistant TB (MDR-TB)—a form of the disease caused by bacilli resistant at least to isoniazid and rifampin—occurred in 2013. Only 28% of these FIGuRE 202-3 Estimated numbers of tuberculosis-related deaths in 2013. (See disclaimer in Fig. 202-2. Courtesy of the Global TB Programme, WHO; with permission.) per year 0–9.9 10–19 20–49 50–124 125–299 300–499 ˜500 No data Not applicable


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 202-2 Estimated tuberculosis (TB) incidence rates (per 100,000 population) in 2013. The designations used and the presentation of material on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization (WHO) concerning the legal status of any country, territory, city, or area or of its authorities or concerning the delimitation of its frontiers or boundaries. Dotted, dashed, and white lines represent approximate border lines for which there may not yet be full agreement. (Courtesy of the Global TB Programme, WHO; with permission.) cases were diagnosed because of a lack of culture and drug-suscep-China, India, the Russian Federation, Pakistan, and Ukraine. Since tibility testing capacity in most settings worldwide. The countries of 2006, 100 countries, including the United States, have reported cases the former Soviet Union have reported the highest proportions of of extensively drug-resistant TB (XDR-TB), in which MDR-TB is MDR


InternalMed_Harrison

InternalMed_Harrison. 100 countries, including the United States, have reported cases the former Soviet Union have reported the highest proportions of of extensively drug-resistant TB (XDR-TB), in which MDR-TB is MDR disease among new TB cases (up to 35–40% in some regions compounded by additional resistance to the most powerful second-of Russia and Belarus). Overall, 60% of all MDR-TB cases occur in line anti-TB drugs (fluoroquinolones and at least one of the injectable


InternalMed_Harrison

InternalMed_Harrison. Number of deaths drugs amikacin, kanamycin, and capreomycin). Up to 10% of the MDR-TB cases worldwide may actually be XDR-TB, but the vast majority of XDR-TB cases remain undiagnosed because reliable methods for drug susceptibility testing are lacking and laboratory capacity is limited. Lately, cases deemed resistant to all anti-TB drugs have been reported from countries such as India, Italy, and Iran; however, this information must be interpreted with caution because drug susceptibility testing for several second-line drugs is neither accurate nor reproducible.


InternalMed_Harrison

InternalMed_Harrison. M. tuberculosis is most commonly transmitted from a person with infectious pulmonary TB by droplet nuclei, which are aerosolized by coughing, sneezing, or speaking. The tiny droplets dry rapidly; the smallest (<5–10 μm in diameter) may remain suspended in the air for several hours and may reach the terminal air passages when inhaled. There may be as many as 3000 infectious nuclei per cough. Other routes of transmission of tubercle bacilli (e.g., through the skin or the placenta) are uncommon and of no epidemiologic significance. The probability of contact with a person who has an infectious form of TB, the intimacy and duration of that contact, the degree of infectiousness of the case, and the shared environment in which the contact takes place are all important determinants of the likelihood of transmission. Several studies of close-contact situations have clearly demonstrated that TB patients whose sputum contains AFB visible by microscopy (sputum smear–positive cases) are the most


InternalMed_Harrison

InternalMed_Harrison. of transmission. Several studies of close-contact situations have clearly demonstrated that TB patients whose sputum contains AFB visible by microscopy (sputum smear–positive cases) are the most likely to transmit the infection. The most infectious patients have cavitary pulmonary disease or, much less commonly, laryngeal TB and produce sputum containing as many as 105–107 AFB/mL. Patients with sputum smear–negative/culturepositive TB are less infectious, although they have been responsible for up to 20% of transmission in some studies in the United States. Those with culture-negative pulmonary TB and extrapulmonary TB are essentially noninfectious. Because persons with both HIV infection and TB are less likely to have cavitations, they may be less infectious than persons without HIV co-infection. Crowding in poorly ventilated rooms is one of the most important factors in the transmission of tubercle bacilli because it increases the intensity of contact with a case.


InternalMed_Harrison

InternalMed_Harrison. The risk of acquiring M. tuberculosis infection is determined mainly by exogenous factors. Because of delays in seeking care and in making a diagnosis, it is generally estimated that, in high-prevalence settings, up to 20 contacts may be infected by each AFB-positive case before the index case is diagnosed.


InternalMed_Harrison

InternalMed_Harrison. Unlike the risk of acquiring infection with M. tuberculosis, the risk of developing disease after being infected depends largely on endogenous factors, such as the individual’s innate immunologic and nonimmunologic defenses and the level at which the individual’s cell-mediated immunity (CMI) is functioning. Clinical illness directly following infection is classified as primary TB and is common among children in the first few years of life and among immunocompromised persons. Although primary TB may be severe and disseminated, it generally is not associated with high-level transmissibility. When infection is acquired later in life, the chance is greater that the mature immune system will contain it at least temporarily. Bacilli, however, may persist for years before reactivating to produce secondary (or postprimary) TB, which, because of frequent cavitation, is more often infectious than is primary disease. Overall, it is estimated that up to 10% of infected persons will eventually


InternalMed_Harrison

InternalMed_Harrison. secondary (or postprimary) TB, which, because of frequent cavitation, is more often infectious than is primary disease. Overall, it is estimated that up to 10% of infected persons will eventually develop active TB in their lifetime—half of them during the first 18 months after infection. The risk is much higher among HIV-infected persons. Reinfection of a previously infected individual, which is common in areas with high rates of TB transmission, may also favor the development of disease. At the height of the TB resurgence in the United States in the early 1990s, molecular typing and comparison of strains of M. tuberculosis suggested that up to one-third of cases of active TB in some inner-city communities were due to recent transmission rather than to reactivation of old latent infection. Age is an important determinant of the risk of disease after infection. Among infected persons, the incidence of TB is highest during late adolescence and early adulthood; the reasons are unclear.


InternalMed_Harrison

InternalMed_Harrison. Age is an important determinant of the risk of disease after infection. Among infected persons, the incidence of TB is highest during late adolescence and early adulthood; the reasons are unclear. The incidence among women peaks at 25–34 years of age. In this age group, rates among women may be higher than those among men, whereas at older ages the opposite is true. The risk increases in the elderly, possibly because of waning immunity and comorbidity.


InternalMed_Harrison

InternalMed_Harrison. A variety of diseases and conditions favor the development of active TB (Table 202-1). In absolute terms, the most potent risk factor for TB among infected individuals is clearly HIV co-infection, which suppresses cellular immunity. The risk that LTBI will proceed to active disease is directly related to the patient’s degree of immunosuppression. In a study of HIV-infected, tuberculin skin test (TST)–positive persons, this risk varied from 2.6 to 13.3 cases/100 person-years and increased as the CD4+ T cell count decreased.


InternalMed_Harrison

InternalMed_Harrison. Studies conducted in various countries before the advent of chemotherapy showed that untreated TB is often fatal. About one-third of patients died within 1 year after diagnosis, and more than 50% died within 5 years. The 5-year mortality rate among sputum smear–positive cases was 65%. Of the survivors at 5 years, ~60% had undergone spontaneous remission, while the remainder were still excreting tubercle bacilli. With effective, timely, and proper chemotherapy, patients have a very high chance of being cured. However, improper use of anti-TB drugs, while reducing mortality rates, may also result in large numbers of chronic infectious cases, often with drug-resistant bacilli.


InternalMed_Harrison

InternalMed_Harrison. The interaction of M. tuberculosis with the human host begins when droplet nuclei containing viable microorganisms propelled into the air by infectious patients are inhaled by a close bystander. Although the majority of inhaled bacilli are trapped in the upper airways and expelled by ciliated mucosal cells, a fraction (usually <10%) reach the alveoli, a unique immunoregulatory environment. There, alveolar macrophages that have not yet been activated (prototypic alternatively activated macrophages) phagocytose the bacilli. Adhesion of mycobacteria to macrophages results largely from binding of the bacterial cell wall to a variety of macrophage cell-surface molecules, including complement receptors, the mannose receptor, the immunoglobulin GFcγ receptor, and type A scavenger receptors. Phagocytosis is enhanced by complement activation leading to opsonization of bacilli with C3 activation products such as C3b and C3bi. (Bacilli are resistant to complement-mediated lysis.) Binding of


InternalMed_Harrison

InternalMed_Harrison. Phagocytosis is enhanced by complement activation leading to opsonization of bacilli with C3 activation products such as C3b and C3bi. (Bacilli are resistant to complement-mediated lysis.) Binding of certain receptors, such as the mannose receptor, regulates 1106 postphagocytic events such as phagosome–lysosome fusion and inflammatory cytokine production. After a phagosome forms, the survival of


InternalMed_Harrison

InternalMed_Harrison. M. tuberculosis within it seems to depend in part on reduced acidification due to lack of assembly of a complete vesicular proton-adenosine triphosphatase. A complex series of events is generated by the bacterial cell-wall lipoglycan lipoarabinomannan (ManLAM). ManLAM inhibits the intracellular increase of Ca2+. Thus, the Ca2+/calmodulin pathway (leading to phagosome–lysosome fusion) is impaired, and the bacilli survive within the phagosomes. The M. tuberculosis phagosome has been found to inhibit the production of phosphatidylinositol 3phosphate (PI3P). Normally, PI3P earmarks phagosomes for membrane sorting and maturation, including phagolysosome formation, which would destroy the bacteria. Bacterial factors have also been found to block the host defense of autophagy, in which the cell sequesters the phagosome in a double-membrane vesicle (autophagosome) that is destined to fuse with lysosomes. If the bacilli are successful in arresting phagosome maturation, then replication begins


InternalMed_Harrison

InternalMed_Harrison. sequesters the phagosome in a double-membrane vesicle (autophagosome) that is destined to fuse with lysosomes. If the bacilli are successful in arresting phagosome maturation, then replication begins and the macrophage eventually ruptures and releases its bacillary contents. Other uninfected phagocytic cells are then recruited to continue the infection cycle by ingesting dying macrophages and their bacillary content, thus in turn becoming infected themselves and expanding the infection.


InternalMed_Harrison

InternalMed_Harrison. M. tuberculosis must be viewed as a complex formed by a multitude of strains that differ in virulence and are capable of producing a variety of manifestations of disease. Since the elucidation of the


InternalMed_Harrison

InternalMed_Harrison. M. tuberculosis genome in 1998, large mutant collections have been generated, and many bacterial genes that contribute to M. tuberculosis virulence have been found. Different patterns of virulence defects have been defined in various animal models—predominantly mice but also guinea pigs, rabbits, and nonhuman primates. The katG gene encodes for a catalase/peroxidase enzyme that protects against oxidative stress and is required for isoniazid activation and subsequent bactericidal activity. Region of difference 1 (RD1) is a 9.5-kb locus that encodes two key small protein antigens—early secretory antigen-6 (ESAT-6) and culture filtrate protein-10 (CFP-10)—as well as a putative secretion apparatus that may facilitate their egress; the absence of this locus in the vaccine strain M. bovis bacille Calmette-Guérin (BCG) has been shown to be a key attenuating mutation. The validity of a recent observation in M. marinum needs to be confirmed in M. tuberculosis; in M. marinum, a mutation in the


InternalMed_Harrison

InternalMed_Harrison. Calmette-Guérin (BCG) has been shown to be a key attenuating mutation. The validity of a recent observation in M. marinum needs to be confirmed in M. tuberculosis; in M. marinum, a mutation in the RD1 virulence locus encoding the ESX1 secretion system impairs the capacity of apoptotic macrophages to recruit uninfected cells for further rounds of infection. The results are less replication and fewer new granulomas. Mutants lacking key enzymes of bacterial biosynthesis become auxotrophic for the missing substrate and often are totally unable to proliferate in animals; these include the leuCD and panCD mutants, which require leucine and pantothenic acid, respectively. The isocitrate lyase gene icl1 encodes a key step in the glyoxylate shunt that facilitates bacterial growth on fatty acid substrates; this gene is required for longterm persistence of M. tuberculosis infection in mice with chronic TB. M. tuberculosis mutants in regulatory genes such as sigma factor C and sigma factor H


InternalMed_Harrison

InternalMed_Harrison. substrates; this gene is required for longterm persistence of M. tuberculosis infection in mice with chronic TB. M. tuberculosis mutants in regulatory genes such as sigma factor C and sigma factor H (sigC and sigH) are associated with normal bacterial growth in mice, but they fail to elicit full tissue pathology. Finally, the mycobacterial protein CarD (expressed by the carD gene) seems essential for the control of rRNA transcription that is required for replication and persistence in the host cell. Its loss exposes mycobacteria to oxidative stress, starvation, DNA damage, and ultimately sensitivity to killing by a variety of host mutagens and defensive mechanisms.


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InternalMed_Harrison. Several observations suggest that genetic factors play a key role in innate nonimmune resistance to infection with M. tuberculosis and the development of disease. The existence of this resistance, which is polygenic in nature, is suggested by the differing degrees of susceptibility to TB in different populations. In mice, a gene called Nramp1 (natural resistance–associated macrophage protein 1) plays a regulatory role in resistance/susceptibility to mycobacteria. The human homologue NRAMP1, which maps to chromosome 2q, may play a role in determining susceptibility to TB, as is suggested by a study among West Africans. Studies of mouse genetics identified a novel host resistance gene, ipr1, which is encoded within the sst1 locus; ipr1 encodes an interferon (IFN)–inducible nuclear protein that interacts with other nuclear proteins in macrophages primed with IFNs or infected by M. tuberculosis. In addition, polymorphisms in multiple genes, such as those encoding for various major


InternalMed_Harrison

InternalMed_Harrison. that interacts with other nuclear proteins in macrophages primed with IFNs or infected by M. tuberculosis. In addition, polymorphisms in multiple genes, such as those encoding for various major histocompatibility complex (MHC) alleles, IFN-γ, T cell growth factor β, interleukin (IL) 10, mannose-binding protein, IFN-γ receptor, Toll-like receptor 2, vitamin D receptor, and IL-1, have been associated with susceptibility to TB.


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InternalMed_Harrison. THE HOST RESPONSE, GRANuLOMA FORMATION, AND “LATENCY”


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InternalMed_Harrison. In the initial stage of host–bacterium interaction, prior to the onset of an acquired CMI response, M. tuberculosis disseminates widely through the lymph vessels, spreading to other sites in the lungs and other organs, and undergoes a period of extensive growth within naïve unactivated macrophages; additional naïve macrophages are recruited to the early granuloma. Studies suggest that M. tuberculosis uses specific virulence mechanisms to subvert host cellular signaling and to elicit an early regulated proinflammatory response that promotes granuloma expansion and bacterial growth during this key early phase. A study of M. marinum infection in zebrafish has delineated one molecular mechanism by which mycobacteria induce granuloma formation. The mycobacterial protein ESAT-6 induces secretion of matrix metalloproteinase 9 (MMP9) by nearby epithelial cells that are in contact with infected macrophages. MMP9 in turn stimulates recruitment of naïve macrophages, thus inducing granuloma


InternalMed_Harrison

InternalMed_Harrison. of matrix metalloproteinase 9 (MMP9) by nearby epithelial cells that are in contact with infected macrophages. MMP9 in turn stimulates recruitment of naïve macrophages, thus inducing granuloma maturation and bacterial growth. Disruption of MMP9 function results in reduced bacterial growth. Another study has shown that M. tuberculosis–derived cyclic AMP is secreted from the phagosome into host macrophages, subverting the cell’s signal transduction pathways and stimulating an elevation in the secretion of tumor necrosis factor α (TNF-α) as well as further proinflammatory cell recruitment. Ultimately, the chemoattractants and bacterial products released during the repeated rounds of cell lysis and infection of newly arriving macrophages enable dendritic cells to access bacilli; these cells migrate to the draining lymph nodes and present mycobacterial antigens to T lymphocytes. At this point, the development of CMI and humoral immunity begins. These initial stages of infection are usually


InternalMed_Harrison

InternalMed_Harrison. to the draining lymph nodes and present mycobacterial antigens to T lymphocytes. At this point, the development of CMI and humoral immunity begins. These initial stages of infection are usually asymptomatic.


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InternalMed_Harrison. About 2–4 weeks after infection, two host responses to M. tuberculosis develop: a macrophage-activating CMI response and a tissue-damaging response. The macrophage-activating response is a T cell–mediated phenomenon resulting in the activation of macrophages that are capable of killing and digesting tubercle bacilli. The tissue-damaging response is the result of a delayed-type hypersensitivity (DTH) reaction to various bacillary antigens; it destroys unactivated macrophages that contain multiplying bacilli but also causes caseous necrosis of the involved tissues (see below). Although both of these responses can inhibit mycobacterial growth, it is the balance between the two that determines the forms of TB that will develop subsequently. With the development of specific immunity and the accumulation of large numbers of activated macrophages at the site of the primary lesion, granulomatous lesions (tubercles) are formed. These lesions consist of accumulations of lymphocytes and


InternalMed_Harrison

InternalMed_Harrison. the accumulation of large numbers of activated macrophages at the site of the primary lesion, granulomatous lesions (tubercles) are formed. These lesions consist of accumulations of lymphocytes and activated macrophages that evolve toward epithelioid and giant cell morphologies. Initially, the tissue-damaging response can limit mycobacterial growth within macrophages. As stated above, this response, mediated by various bacterial products, not only destroys macrophages but also produces early solid necrosis in the center of the tubercle. Although M. tuberculosis can survive, its growth is inhibited within this necrotic environment by low oxygen tension and low pH. At this point, some lesions may heal by fibrosis, with subsequent calcification, whereas inflammation and necrosis occur in other lesions. Some observations have challenged the traditional view that any encounter between mycobacteria and macrophages results in chronic infection. It is possible that an immune response capable


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InternalMed_Harrison. lesions. Some observations have challenged the traditional view that any encounter between mycobacteria and macrophages results in chronic infection. It is possible that an immune response capable of eradicating early infection may sometimes develop as a consequence, for instance, of disabling mutations in mycobacterial genomes rendering their replication ineffective. Individual granulomas that are formed during this phase of infection can vary in size and cell composition; some can contain the spread of mycobacteria, while others cannot. LTBI ensues as a result of this dynamic balance between the microorganism and the host. According to recent developments, latency may not be an accurate term because bacilli may remain active during this “latent” stage, forming biofilms in necrotic areas within which they temporarily hide. Thus, the term persister is probably more accurate to indicate the behavior of the bacilli in this phase. It is important to recognize that latent infection and


InternalMed_Harrison

InternalMed_Harrison. within which they temporarily hide. Thus, the term persister is probably more accurate to indicate the behavior of the bacilli in this phase. It is important to recognize that latent infection and disease represent not a binary state but rather a continuum along which infection will eventually move in the direction of full containment or disease. The ability to predict, through systemic biomarkers, which affected individuals will progress toward disease would be of immense value in devising prophylactic interventions.


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InternalMed_Harrison. CMI is critical at this early stage. In the majority of infected individuals, local macrophages are activated when bacillary antigens processed by macrophages stimulate T lymphocytes to release a variety of lymphokines. These activated macrophages aggregate around the lesion’s center and effectively neutralize tubercle bacilli without causing further tissue destruction. In the central part of the lesion, the necrotic material resembles soft cheese (caseous necrosis)—a phenomenon that may also be observed in other conditions, such as neoplasms. Even when healing takes place, viable bacilli may remain dormant within macrophages or in the necrotic material for many years. These “healed” lesions in the lung parenchyma and hilar lymph nodes may later undergo calcification.


InternalMed_Harrison

InternalMed_Harrison. In a minority of cases, the macrophage-activating response is weak, and mycobacterial growth can be inhibited only by intensified DTH reactions, which lead to lung tissue destruction. The lesion tends to enlarge further, and the surrounding tissue is progressively damaged. At the center of the lesion, the caseous material liquefies. Bronchial walls and blood vessels are invaded and destroyed, and cavities are formed. The liquefied caseous material, containing large numbers of bacilli, is drained through bronchi. Within the cavity, tubercle bacilli multiply, spill into the airways, and are discharged into the environment through expiratory maneuvers such as coughing and talking. In the early stages of infection, bacilli are usually transported by macrophages to regional lymph nodes, from which they gain access to the central venous return; from there they reseed the lungs and may also disseminate beyond the pulmonary vasculature throughout the body via the systemic circulation. The


InternalMed_Harrison

InternalMed_Harrison. which they gain access to the central venous return; from there they reseed the lungs and may also disseminate beyond the pulmonary vasculature throughout the body via the systemic circulation. The resulting extrapulmonary lesions may undergo the same evolution as those in the lungs, although most tend to heal. In young children with poor natural immunity, hematogenous dissemination may result in highly fatal miliary TB or tuberculous meningitis.


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InternalMed_Harrison. While CMI confers partial protection against M. tuberculosis, humoral immunity plays a less well-defined role in protection (although evidence is accumulating on the existence of antibodies to lipoarabinomannan, which may prevent dissemination of infection in children). In the case of CMI, two types of cells are essential: macrophages, which directly phagocytose tubercle bacilli, and T cells (mainly CD4+ T lymphocytes), which induce protection through the production of cytokines, especially IFN-γ. After infection with M. tuberculosis, alveolar macrophages secrete various cytokines responsible for a number of events (e.g., the formation of granulomas) as well as systemic effects (e.g., fever and weight loss). However, alternatively activated alveolar macrophages may be particularly susceptible to M. tuberculosis growth early on, given their more limited proinflammatory and bactericidal activity, which is related in part to being bathed in surfactant. New monocytes and macrophages


InternalMed_Harrison

InternalMed_Harrison. to M. tuberculosis growth early on, given their more limited proinflammatory and bactericidal activity, which is related in part to being bathed in surfactant. New monocytes and macrophages attracted to the site are key components of the immune response. Their primary mechanism is probably related to production of oxidants (such as reactive oxygen intermediates or nitric oxide) that have antimycobacterial activity and increase the synthesis of cytokines such as TNF-α and IL-1, which in turn regulate the release of reactive oxygen intermediates and reactive nitrogen intermediates. In addition, macrophages can undergo apoptosis—a defensive mechanism to prevent release of cytokines and bacilli via their sequestration in the apoptotic cell. Recent work also describes the involvement of neutrophils in the host response, although the timing 1107 of their appearance and their effectiveness remain uncertain.


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InternalMed_Harrison. Alveolar macrophages, monocytes, and dendritic cells are also critical in processing and presenting antigens to T lymphocytes, primarily CD4+ and CD8+ T cells; the result is the activation and proliferation of CD4+ T lymphocytes, which are crucial to the host’s defense against


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InternalMed_Harrison. M. tuberculosis. Qualitative and quantitative defects of CD4+ T cells explain the inability of HIV-infected individuals to contain mycobacterial proliferation. Activated CD4+ T lymphocytes can differentiate into cytokine-producing TH1 or TH2 cells. TH1 cells produce IFN-γ—an activator of macrophages and monocytes—and IL-2. TH2 cells produce IL-4, IL-5, IL-10, and IL-13 and may also promote humoral immunity. The interplay of these various cytokines and their cross-regulation determine the host’s response. The role of cytokines in promoting intracellular killing of mycobacteria, however, has not been entirely elucidated. IFN-γ may induce the generation of reactive nitrogen intermediates and regulate genes involved in bactericidal effects. TNF-α also seems to be important. Observations made originally in transgenic knockout mice and more recently in humans suggest that other T cell subsets, especially CD8+ T cells, may play an important role. CD8+ T cells have been associated with


InternalMed_Harrison

InternalMed_Harrison. made originally in transgenic knockout mice and more recently in humans suggest that other T cell subsets, especially CD8+ T cells, may play an important role. CD8+ T cells have been associated with protective activities via cytotoxic responses and lysis of infected cells as well as with production of IFN-γ and TNF-α. Finally, natural killer cells act as co-regulators of CD8+ T cell lytic activities, and γδ T cells are increasingly thought to be involved in protective responses in humans.


InternalMed_Harrison

InternalMed_Harrison. Lipids have been involved in mycobacterial recognition by the innate immune system, and lipoproteins (such as 19-kDa lipoprotein) have been proven to trigger potent signals through Toll-like receptors present in blood dendritic cells. M. tuberculosis possesses various protein antigens. Some are present in the cytoplasm and cell wall; others are secreted. That the latter are more important in eliciting a T lymphocyte response is suggested by experiments documenting the appearance of protective immunity in animals after immunization with live, protein-secreting mycobacteria. Among the antigens that may play a protective role are the 30-kDa (or 85B) and ESAT-6 antigens. Protective immunity is probably the result of reactivity to many different mycobacterial antigens. These antigens are being incorporated into newly designed vaccines on various platforms.


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InternalMed_Harrison. Coincident with the appearance of immunity, DTH to M. tuberculosis develops. This reactivity is the basis of the TST, which is used primarily for the detection of M. tuberculosis infection in persons without symptoms. The cellular mechanisms responsible for TST reactivity are related mainly to previously sensitized CD4+ T lymphocytes, which are attracted to the skin-test site. There, they proliferate and produce cytokines. Although DTH is associated with protective immunity (TST-positive persons are less susceptible to a new M. tuberculosis infection than TST-negative persons), it by no means guarantees protection against reactivation. In fact, cases of active TB are often accompanied by strongly positive skin-test reactions. There is also evidence of reinfection with a new strain of M. tuberculosis in patients previously treated for active disease. This evidence underscores the fact that previous latent or active TB may not confer fully protective immunity.


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InternalMed_Harrison. TB is classified as pulmonary, extrapulmonary, or both. Depending on several factors linked to different populations and bacterial strains, extrapulmonary TB may occur in 10–40% of patients. Furthermore, up to two-thirds of HIV-infected patients with TB may have both pulmonary and extrapulmonary TB or extrapulmonary TB alone. Pulmonary TB is conventionally categorized as primary or postprimary (adult-type, secondary). This distinction has been challenged 1108 by molecular evidence from TB-endemic areas indicating that a large percentage of cases of adult pulmonary TB result from recent infection (either primary infection or reinfection) and not from reactivation.


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InternalMed_Harrison. Primary Disease Primary pulmonary TB occurs soon after the initial infection with tubercle bacilli. It may be asymptomatic or may present with fever and occasionally pleuritic chest pain. In areas of high TB transmission, this form of disease is often seen in children. Because most inspired air is distributed to the middle and lower lung zones, these areas are most commonly involved in primary TB. The lesion forming after initial infection (Ghon focus) is usually peripheral and accompanied by transient hilar or paratracheal lymphadenopathy, which may or may not be visible on standard chest radiography (Fig. 202-4). Some patients develop erythema nodosum on the legs (see Fig. 25e-40) or phlyctenular conjunctivitis. In the majority of cases, the lesion heals spontaneously and becomes evident only as a small calcified nodule. Pleural reaction overlying a subpleural focus is also common. The Ghon focus, with or without overlying pleural reaction, thickening, and regional lymphadenopathy,


InternalMed_Harrison

InternalMed_Harrison. only as a small calcified nodule. Pleural reaction overlying a subpleural focus is also common. The Ghon focus, with or without overlying pleural reaction, thickening, and regional lymphadenopathy, is referred to as the Ghon complex.


InternalMed_Harrison

InternalMed_Harrison. In young children with immature CMI and in persons with impaired immunity (e.g., those with malnutrition or HIV infection), primary pulmonary TB may progress rapidly to clinical illness. The initial lesion increases in size and can evolve in different ways. Pleural effusion, which is found in up to two-thirds of cases, results from the penetration of bacilli into the pleural space from an adjacent subpleural focus. In severe cases, the primary site rapidly enlarges, its central portion undergoes necrosis, and cavitation develops (progressive primary TB). TB in young children is almost invariably accompanied by hilar or paratracheal lymphadenopathy due to the spread of bacilli from the lung parenchyma through lymphatic vessels. Enlarged lymph nodes may compress bronchi, causing total obstruction with distal collapse, partial obstruction with large-airway wheezing, or a ball-valve effect with segmental/lobar hyperinflation. Lymph nodes may also rupture into the airway with development


InternalMed_Harrison

InternalMed_Harrison. with distal collapse, partial obstruction with large-airway wheezing, or a ball-valve effect with segmental/lobar hyperinflation. Lymph nodes may also rupture into the airway with development of pneumonia, often including areas of necrosis and cavitation, distal to the obstruction. Bronchiectasis (Chap. 312) may develop in any segment/lobe damaged by progressive caseating pneumonia. Occult hematogenous dissemination commonly follows primary infection. However, in the absence of a sufficient acquired immune response, which usually contains the infection, disseminated or miliary disease may result (Fig. 202-5). Small granulomatous lesions develop in multiple organs and may cause locally progressive disease or result in tuberculous meningitis; this is a particular concern in very young children and immunocompromised persons (e.g., patients with HIV infection).


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InternalMed_Harrison. FIGuRE 202-4 Chest radiograph showing right hilar lymph node enlargement with infiltration into the surrounding lung tissue in a child with primary tuberculosis. (Courtesy of Prof. Robert Gie, Department of Paediatrics and Child Health, Stellenbosch University, South Africa; with permission.) FIGuRE 202-5 Chest radiograph showing bilateral miliary (millet-sized) infiltrates in a child. (Courtesy of Prof. Robert Gie, Department of Paediatrics and Child Health, Stellenbosch University, South Africa; with permission.)


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InternalMed_Harrison. Postprimary (Adult-Type) Disease Also referred to as reactivation or secondary TB, postprimary TB is probably most accurately termed adult-type TB because it may result from endogenous reactivation of distant LTBI or recent infection (primary infection or reinfection). It is usually localized to the apical and posterior segments of the upper lobes, where the substantially higher mean oxygen tension (compared with that in the lower zones) favors mycobacterial growth. The superior segments of the lower lobes are also more frequently involved. The extent of lung parenchymal involvement varies greatly, from small infiltrates to extensive cavitary disease. With cavity formation, liquefied necrotic contents are ultimately discharged into the airways and may undergo bronchogenic spread, resulting in satellite lesions within the lungs that may in turn undergo cavitation (Figs. 202-6 and 202-7). Massive involvement of pulmonary segments or lobes, with coalescence of lesions, produces caseating


InternalMed_Harrison

InternalMed_Harrison. in satellite lesions within the lungs that may in turn undergo cavitation (Figs. 202-6 and 202-7). Massive involvement of pulmonary segments or lobes, with coalescence of lesions, produces caseating pneumonia. While up to one-third of untreated patients reportedly succumb to severe pulmonary TB within a few months after onset (the classic “galloping consumption” of the past), others may undergo a process of spontaneous remission or proceed along a chronic, progressively debilitating course (“consumption” or phthisis). Under these circumstances, some pulmonary lesions become fibrotic and may later calcify, but cavities persist in other parts of the lungs. Individuals with such chronic disease continue to discharge tubercle bacilli into the environment. Most patients respond to treatment, with defervescence, decreasing cough, weight gain, and a general improvement in well-being within several weeks.


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InternalMed_Harrison. Early in the course of disease, symptoms and signs are often nonspecific and insidious, consisting mainly of diurnal fever and night sweats due to defervescence, weight loss, anorexia, general malaise, and weakness. However, in up to 90% of cases, cough eventually develops—often initially nonproductive and limited to the morning and subsequently accompanied by the production of purulent sputum, sometimes with blood streaking. Hemoptysis develops in 20–30% of cases, and massive hemoptysis may ensue as a consequence of the erosion of a blood vessel in the wall of a cavity. Hemoptysis, however, may also result from rupture of a dilated vessel in a cavity (Rasmussen’s aneurysm) or from aspergilloma formation in an old cavity. Pleuritic chest pain sometimes develops in patients with subpleural parenchymal lesions or pleural disease. Extensive disease may produce dyspnea and, in rare instances, adult respiratory distress syndrome. Physical findings are of limited use in pulmonary TB. Many