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InternalMed_Harrison. In adults, a food history and the names of contacts who may have shared foods should be obtained before illness progresses to respiratory failure; specific questions should include information about the consumption of home-preserved and/or exotic foods and of products requiring refrigeration that have been left at room temperature in sealed plastic containers or bags. A history of recent consumption of home-canned food substantially enhances the probability of food-borne botulism. Ascertainment of the patient’s behavioral history related to injection drug use is critical to the diagnosis of wound botulism unless an accidental wound is evident. Caretakers’ observations up to and including the onset of symptoms are vital to the diagnosis of infant botulism. A history of recent abdominal surgery or antibiotic use may be important in the diagnosis of adult intestinal colonization botulism.


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InternalMed_Harrison. Differential Diagnosis The illnesses most commonly considered in the differential diagnosis of adult botulism cases include Guillain-Barré syndrome (GBS), myasthenia gravis, stroke syndromes, Eaton-Lambert syndrome, and tick paralysis. Less likely possibilities are poisoning by tetrodotoxin, shellfish, or a host of rarer agents and antimicrobial drug–associated paralysis. A thorough history and a meticulous physical examination can effectively eliminate most alternative diagnoses, but a workup for other diagnoses should not delay treatment with botulinum antitoxin.


InternalMed_Harrison

InternalMed_Harrison. GBS, a rare autoimmune demyelinating polyneuropathy that often follows an acute infection, presents most often as an ascending paralysis. Case clusters are rare. Occasional GBS cases present as the Miller Fisher variant, whose characteristic triad of ophthalmoplegia, ataxia, and areflexia is easily mistaken for the early descending paralysis of botulism. Protein levels in cerebrospinal fluid (CSF) are elevated in GBS; because this increase may be delayed until several days after symptom onset, an early lumbar puncture with a negative result may need to be repeated. In contrast, CSF findings are generally normal in botulism, although marginally elevated CSF protein concentrations have been reported. In experienced hands, electromyography may differentiate GBS from botulism. The edrophonium (Tensilon) test is sometimes of value in distinguishing botulism (usually a negative result) from myasthenia gravis (usually a positive result).


InternalMed_Harrison

InternalMed_Harrison. The edrophonium (Tensilon) test is sometimes of value in distinguishing botulism (usually a negative result) from myasthenia gravis (usually a positive result). In most cerebrovascular accidents, physical examination reveals asymmetry of paralysis and upper motor neuron signs. Brain imaging can reveal the rare basilar stroke that produces symmetric bulbar palsies. Eaton-Lambert syndrome usually manifests as proximal limb weakness in a patient already debilitated by cancer. Tick paralysis is a rare flaccid condition closely resembling botulism and caused by neurotoxins of certain ticks.


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InternalMed_Harrison. Botulism-Specific Laboratory Tests Botulism is confirmed in the laboratory by demonstration of toxin in clinical specimens (e.g., serum, stool, gastric aspirate, and sterile-water enema samples) or in samples of ingested foods. Isolation of toxigenic clostridia from stool also provides evidence of botulism. Wound cultures yielding the organism are highly suggestive in symptomatic cases. The universally accepted method for confirmation of botulism is the mouse bioassay, which is available only in specialized laboratories. Specific guidance about what specimens to collect should be obtained from the testing laboratory because the requirements vary with the form of botulism suspected. Clinical specimens collected early in the hospital admission process should be submitted for testing; toxin results may be negative if specimens are collected >7 days after symptom onset. Because of the extreme potency of botulinum toxin, a test may yield a negative result even when a patient has botulism;


InternalMed_Harrison

InternalMed_Harrison. results may be negative if specimens are collected >7 days after symptom onset. Because of the extreme potency of botulinum toxin, a test may yield a negative result even when a patient has botulism; thus, a negative result does not exclude this diagnosis. In suspected wound botulism, material from abscesses should be collected in anaerobic culture tubes. New laboratory tests for botulism are being developed but remain experimental. Nerve conduction studies showing reduced amplitude of motor potentials—with or without potentiation by rapid repetitive stimulation in weak muscles—and needle electromyography showing small-motor-unit action potentials are consistent with botulism; these results and those that make alternative diagnoses more likely may be useful. Standard blood work and radiologic studies are not useful in diagnosing botulism.


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InternalMed_Harrison. The cornerstones of treatment for botulism are meticulous intensive care and immediate administration of botulinum antitoxin. Because antitoxin is most beneficial early in the course of clinical illness, it should be administered as soon as botulism is suspected and before the time-consuming workup for other illnesses is complete. Persons of all ages (including infants) in whom botulism is suspected should be hospitalized immediately so that respiratory failure—the usual cause of death—can be detected and man-989 aged promptly. Vital capacity should be monitored frequently and mechanical ventilation provided as needed. Botulinum antitoxin can limit the progression of illness because it neutralizes toxin molecules in the circulation that have not yet bound to nerve endings. However, antitoxin does not reverse existing paralysis, which may take weeks to improve. In the United States, there are two licensed antitoxin products: Botulism Antitoxin Heptavalent® (BAT; Emergent Biosolutions,


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InternalMed_Harrison. does not reverse existing paralysis, which may take weeks to improve. In the United States, there are two licensed antitoxin products: Botulism Antitoxin Heptavalent® (BAT; Emergent Biosolutions, Rockville, MD), an equine-derived heptavalent (A through G) product enzymatically de-speciated for treatment of all forms of adult botulism and infant cases not involving serotypes A and B; and Botulism Immune Globulin Intravenous (BabyBIG®; California Department of Public Health, Sacramento, CA), a human-derived product for treating infant botulism caused by serotype A and/or B only. Antitoxin is also available in some other countries. Aminoglycosides and other medications that block the neuromuscular junction may potentiate botulism and should be avoided.


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InternalMed_Harrison. In wound botulism, suspect wounds and abscesses should be cleaned, debrided, and drained promptly. The role of penicillin and metronidazole in treatment and decolonization is unclear. It has been hypothesized that antimicrobial agents may increase circulating botulinum toxin from lysis of bacterial cells. Person-to-person transmission of botulism does not occur. Universal precautions are the only infection-control measures required during inpatient care. NOTIFICATION, EXPERT CONSULTATION, AND ANTITOXIN PROVISION Every botulism case is a public health emergency. Antitoxin is not universally available. Some countries maintain stockpiles of antitoxin for immediate response, whereas others must access supplies from other nations when an outbreak occurs.


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InternalMed_Harrison. In the United States, clinicians must report every suspected case, regardless of form, on an emergency basis to their state health department. The state health department may put the physician in contact with the 24/7 botulism consultation service at the Centers for Disease Control and Prevention (CDC) through the CDC Emergency Operations Center (770-488-7100) or a locally available service. The botulism consultant will review the case and determine whether botulism is likely. If indicated, the consultant will coordinate laboratory confirmation at appropriate testing facilities and facilitate emergency shipment of antitoxin for all adult cases and for infant cases not involving serotypes A and B. In this country, botulinum antitoxin for noninfant cases is available exclusively from the CDC. Physicians who see suspected infant botulism cases should contact the California Department of Public Health Infant Botulism Treatment and Prevention Program (510-231-7600), which provides 24-h


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InternalMed_Harrison. CDC. Physicians who see suspected infant botulism cases should contact the California Department of Public Health Infant Botulism Treatment and Prevention Program (510-231-7600), which provides 24-h consultation and distributes antitoxin (BabyBIG) for the treatment of infant botulism nationwide. Except in cases involving infants who reside in California, laboratory testing requests must still be authorized by the state health department where the infant is located or by the CDC.


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InternalMed_Harrison. No prophylaxis or licensed vaccine is available against botulism. Home-canning instructions and equipment have changed over the years. Up-to-date canning instructions from reliable sources (e.g., the U.S. Department of Agriculture or the U.S. Food and Drug Administration) should be followed to ensure food safety. Processed food should be stored properly and heated thoroughly prior to consumption. Because of the possible presence of spores, honey should not be given to infants (≤12 months of age). Injection of illicit drugs should be avoided. All wounds should be meticulously cleaned to eliminate possible contamination with bacterial spores. Clinicians should educate individuals or family members of at-risk individuals, including infants, illegal drug users, and preparers of home-preserved foods. The authors thank Dr. Jeremy Sobel for his valued contributions to the previous version of this chapter.


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InternalMed_Harrison. The authors thank Dr. Jeremy Sobel for his valued contributions to the previous version of this chapter. 990 gas gangrene and other Clostridial Infections Amy E. Bryant, Dennis L. Stevens The genus Clostridium encompasses more than 60 species that may be commensals of the gut microflora or may cause a variety of infections in humans and animals through the production of a plethora of pro-179 teinaceous exotoxins. C. tetani and C. botulinum, for example, cause specific clinical disease by elaborating single but highly potent toxins. In contrast, C. perfringens and C. septicum cause aggressive necrotizing infections that are attributable to multiple toxins, including bacterial proteases, phospholipases, and cytotoxins.


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InternalMed_Harrison. Vegetative cells of Clostridium species are pleomorphic, rod-shaped, and arranged singly or in short chains (Fig. 179-1); the cells have rounded or sometimes pointed ends. Although clostridia stain gram-positive in the early stages of growth, they may appear to be gram-negative or gram-variable later in the growth cycle or in infected tissue specimens. Most strains are motile by means of peritrichous flagella; C. septicum swarms on solid media. Nonmotile species include C. perfringens, C. ramosum, and C. innocuum. Most species are obligately anaerobic, although clostridial tolerance to oxygen varies widely; some species (e.g., C. septicum, C. tertium) will grow but will not sporulate in air.


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InternalMed_Harrison. Clostridia produce more protein toxins than any other bacterial genus, and more than 25 clostridial toxins lethal to mice have been identified. These proteins include neurotoxins, enterotoxins, cytotoxins, collagenases, permeases, necrotizing toxins, lipases, lecithinases, hemolysins, proteinases, hyaluronidases, DNases, ADPribosyltransferases, and neuraminidases. Botulinum and tetanus neurotoxins are the most potent toxins known, with lethal doses of 0.2–10 ng/kg for humans. Epsilon toxin, a 33-kDa protein produced by C. perfringens types B and D, causes edema and hemorrhage in the brain, heart, spinal cord, and kidneys of animals. It is among the most lethal of the clostridial toxins and is considered a potential agent of bioterrorism (Chap. 261e). The genomic sequences of some pathogenic clostridia are now available and are likely to facilitate a comprehensive approach to understanding the virulence factors involved in clostridial pathogenesis.


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InternalMed_Harrison. Clostridium species are widespread in nature, forming endospores that are commonly found in soil, feces, sewage, and marine sediments. The ecology of C. perfringens in soil is greatly influenced by the degree and duration of animal husbandry in a given location and is relevant to the incidence of gas gangrene caused by contamination of war wounds with soil. For example, the incidence of clostridial gas gangrene is higher in agricultural regions of Europe than in the Sahara Desert of Africa. Similarly, the incidences of tetanus and food-borne botulism are clearly related to the presence of clostridial spores in soil, water, and many foods. Clostridia are present in large numbers in the indigenous microbiota of the intestinal tract of humans and animals, in the female genital tract, and on the oral mucosa. It should be noted that not all commensal clostridia are toxigenic. FIGURE 179-1 Scanning electron micrograph of C. perfringens.


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InternalMed_Harrison. worldwide. In developing nations, food poisoning, necrotizing enterocolitis, and gas gangrene are common because large portions of the population are poor and have little or no immediate access to health care. These infections remain prevalent in developed countries as well. Gas gangrene commonly follows knife or gunshot wounds or vehicular accidents or develops as a complication of surgery or gastrointestinal carcinoma. Severe clostridial infections have emerged as a health threat to injection drug users and to women undergoing childbirth or abortion. Historically, clostridial gas gangrene has been the scourge of the battlefield. The global political situation portends another possible scenario involving mass casualties of war or terrorism, with extensive injuries conducive to gas gangrene. Thus there is an ongoing need to develop novel strategies to prevent or attenuate the course of clostridial infections in both civilians and military personnel. Vaccination against exotoxins


InternalMed_Harrison

InternalMed_Harrison. Thus there is an ongoing need to develop novel strategies to prevent or attenuate the course of clostridial infections in both civilians and military personnel. Vaccination against exotoxins important in pathogenesis would be of great benefit in developing nations and could also be used safely in at-risk populations such as the elderly, patients with diabetes who may require lower-limb surgery due to trauma or poor circulation, and those undergoing intestinal surgery. Moreover, a hyperimmune globulin would be a valuable tool for prophylaxis in victims of acute traumatic injury or for attenuation of the spread of infection in patients with established gas gangrene.


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InternalMed_Harrison. Life-threatening clostridial infections range from intoxications (e.g., food poisoning, tetanus) to necrotizing enteritis/colitis, bacteremia, myonecrosis, and toxic shock syndrome (TSS). Tetanus and botulism are discussed in Chaps. 177 and 178, respectively. Colitis due to C. difficile is discussed in Chap. 161. Of open traumatic wounds, 30–80% reportedly are contaminated with clostridial species. In the absence of devitalized tissue, the presence of clostridia does not necessarily lead to infection. In traumatic injuries, clostridia are isolated with equal frequency from both suppurative and well-healing wounds. Thus, diagnosis and treatment of clostridial infection should be based on clinical signs and symptoms and not solely on bacteriologic findings.


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InternalMed_Harrison. Clostridial species may be found in polymicrobial infections also involving microbial components of the indigenous flora. In these infections, clostridia often appear in association with non-spore-forming anaerobes and facultative or aerobic organisms. Head and neck infections, conjunctivitis, brain abscess, sinusitis, otitis, aspiration pneumonia, lung abscess, pleural empyema, cholecystitis, septic arthritis, and bone infections all may involve clostridia. These conditions are often associated with severe local inflammation but may lack the characteristic systemic signs of toxicity and rapid progression seen in other clostridial infections. In addition, clostridia are isolated from ~66% of intraabdominal infections in which the mucosal integrity of the bowel or respiratory system has been compromised. In this setting, C. ramosum, C. perfringens, and C. bifermentans are the most commonly isolated species. Their presence does not invariably lead to a poor outcome. Clostridia have been


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InternalMed_Harrison. compromised. In this setting, C. ramosum, C. perfringens, and C. bifermentans are the most commonly isolated species. Their presence does not invariably lead to a poor outcome. Clostridia have been isolated from suppurative infections of the female genital tract (e.g., ovarian or pelvic abscess) and from diseased gallbladders. Although the most frequently isolated species is C. perfringens, gangrene is not typically observed; however, gas formation in the biliary system can lead to emphysematous cholecystitis, especially in diabetic patients. C. perfringens in association with mixed aerobic and anaerobic microbes can cause aggressive life-threatening type I necrotizing fasciitis or Fournier’s gangrene.


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InternalMed_Harrison. The treatment of mixed aerobic/anaerobic infection of the abdomen, perineum, or gynecologic organs should be based on Gram’s staining, culture, and antibiotic sensitivity information. Reasonable empirical treatment consists of ampicillin or ampicillin/sulbactam combined with either clindamycin or metronidazole (Table 179-1). Broader gram-negative coverage may be necessary if the patient has recently been hospitalized or treated with antibiotics. Such coverage can be obtained by substituting ticarcillin/clavulanic acid, piperacillin/sulbactam, or a penem antibiotic for ampicillin or by adding a fluoroquinolone or an aminoglycoside to the regimen. Empirical treatment should be given for 10–14 days or until the patient’s clinical condition improves.


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InternalMed_Harrison. C. perfringens type A is one of the most common bacterial causes of food-borne illness in the United States and Canada. The foods typically implicated include improperly cooked meat and meat products (e.g., gravy) in which residual spores germinate and proliferate during slow cooling or insufficient reheating. Illness results from the ingestion of food containing at least ~108 viable vegetative cells, which sporulate in the alkaline environment of the small intestine, producing


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InternalMed_Harrison. C. perfringens enterotoxin in the process. The diarrhea that develops within 7–30 h of ingestion of contaminated food is generally mild and self-limiting; however, in the very young, the elderly, and the immunocompromised, symptoms are more severe and occasionally fatal. Enterotoxin-producing C. perfringens has been implicated as an etiologic agent of persistent diarrhea in elderly patients in nursing homes and tertiary-care institutions and has been considered to play a role in antibiotic-associated diarrhea without pseudomembranous colitis.


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InternalMed_Harrison. C. perfringens strains associated with food poisoning possess the gene (cpe) coding for enterotoxin, which acts by forming pores in host cell membranes. C. perfringens strains isolated from non food-borne diseases, such as antibiotic-associated and sporadic diarrhea, carry cpe on a plasmid that may be transmitted to other strains. Several methods have been described for the detection of C. perfringens enterotoxin in feces, including cell culture assay (Vero cells), enzyme-linked immunosorbent assay, reversed-phase latex agglutination, and polymerase chain reaction (PCR) amplification of cpe. Each method has its advantages and limitations.


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InternalMed_Harrison. Enteritis necroticans (gas gangrene of the bowel) is a fulminating clinical illness characterized by extensive necrosis of the intestinal mucosa and wall. Cases can occur sporadically in adults or as epidemics in people of all ages. Enteritis necroticans is 991 caused by α toxin– and β toxin–producing strains of C. perfringens type C; β toxin is located on a plasmid and is mainly responsible for pathogenesis. This life-threatening infection causes ischemic necrosis of the jejunum. In Papua New Guinea during the 1960s, enteritis necroticans (known in that locale as pigbel) was found to be the most common cause of death in childhood; it was associated with pig feasts and occurred both sporadically and in outbreaks. Intramuscular immunization against the β toxin resulted in a decreased incidence of the disease in Papua New Guinea, although the condition remains common. Enteritis necroticans has also been recognized in the United States, the United Kingdom, Germany (where it is known as


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InternalMed_Harrison. of the disease in Papua New Guinea, although the condition remains common. Enteritis necroticans has also been recognized in the United States, the United Kingdom, Germany (where it is known as darmbrand), and other developed nations; especially affected are adults who are malnourished or who have diabetes, alcoholic liver disease, or neutropenia.


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InternalMed_Harrison. Necrotizing enterocolitis, a disease resembling enteritis necroticans but associated with C. perfringens type A, has been found in North America in previously healthy adults. It is also a serious gastrointestinal disease of low-birth-weight (premature) infants hospitalized in neonatal intensive care units. The etiology and pathogenesis of this disease have remained enigmatic for more than four decades. Pathologic similarities between necrotizing enterocolitis and enteritis necroticans include the pattern of small-bowel necrosis involving the submucosa, mucosa, and muscularis; the presence of gas dissecting the tissue planes; and the degree of inflammation. In contrast to enteritis necroticans, which most commonly involves the jejunum, necrotizing enterocolitis affects the ileum and frequently the ileocecal valve. Both diseases may manifest as intestinal gas cysts, although this feature is more common in necrotizing enterocolitis. The sources of the gas, which contains hydrogen,


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InternalMed_Harrison. frequently the ileocecal valve. Both diseases may manifest as intestinal gas cysts, although this feature is more common in necrotizing enterocolitis. The sources of the gas, which contains hydrogen, methane, and carbon dioxide, are probably the fermentative activities of intestinal bacteria, including clostridia. Epidemiologic data support an important role for C. perfringens or other gas-producing microorganisms (e.g., C. neonatale, certain other clostridia, or Klebsiella species) in the pathogenesis of necrotizing enterocolitis.


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InternalMed_Harrison. Patients with suspected clostridial enteric infection should undergo nasogastric suction and receive IV fluids. Pyrantel is given by mouth, and the bowel is rested by fasting. Benzylpenicillin (1 mU) is given IV every 4 h, and the patient is observed for complications requiring surgery. Patients with mild cases recover without surgical intervention. If surgical indications are present (gas in the peritoneal cavity, absent bowel sounds, rebound tenderness, abdominal rigidity), however, the mortality rate ranges from 35% to 100%; a fatal outcome is due in part to perforation of the intestine. As pigbel continues to be a common disease in Papua New Guinea, consideration should be given to the use of a C. perfringens Polymicrobial anaerobic infections involving clostridia (e.g., abdominal wall, gynecologic) Ciprofloxacin (400 mg IV q6–8 h) Penicillin, 3–4 mU IV q4–6h


InternalMed_Harrison

InternalMed_Harrison. Polymicrobial anaerobic infections involving clostridia (e.g., abdominal wall, gynecologic) Ciprofloxacin (400 mg IV q6–8 h) Penicillin, 3–4 mU IV q4–6h Clindamycin (600–900 mg IV q6–8h) Treatment should be based on clinical signs and symptoms as listed below and not solely on bacteriologic findings. Empirical therapy should be initiated. Therapy should be based on Gram’s stain and culture results and on sensitivity data when available. Add gram-negative coverage if indicated (see text). Transient bacteremia without signs of systemic toxicity may be clinically insignificant. Emergent surgical exploration and thorough debridement are extremely important. Hyperbaric oxygen therapy may be considered after surgery and antibiotic initiation. 992 type C β toxoid vaccine in local areas. Two doses given 3–4 months apart are preventive.


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InternalMed_Harrison. 992 type C β toxoid vaccine in local areas. Two doses given 3–4 months apart are preventive. Clostridium species are important causes of bloodstream infections. Molecular epidemiologic studies of anaerobic bacteremia have identified C. perfringens and C. tertium as the two most frequently isolated species; these organisms cause up to 79% and 5%, respectively, of clostridial bacteremias. Occasionally, C. perfringens bacteremia occurs in the absence of an identifiable infection at another site. When associated with myonecrosis, bacteremia has a grave prognosis.


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InternalMed_Harrison. C. septicum is also commonly associated with bacteremia. This species is isolated only rarely from the feces of healthy individuals but may be found in the normal appendix. More than 50% of patients whose blood cultures are positive for this organism have some gastrointestinal anomaly (e.g., diverticular disease) or underlying malignancy (e.g., carcinoma of the colon). In addition, a clinically important association of C. septicum bacteremia with neutropenia of any origin—and, more specifically, with neutropenic enterocolitis involving the terminal ileum or cecum—has been observed. Patients with diabetes mellitus, severe atherosclerotic cardiovascular disease, or anaerobic myonecrosis (gas gangrene) also may develop C. septicum bacteremia. C. septicum has been recovered from the bloodstream of cirrhotic patients, as have C. perfringens, C. bifermentans, and other clostridia. Infections of the bloodstream by C. sordellii and C. perfringens have been associated with TSS.


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InternalMed_Harrison. Bloodstream infection by C. tertium, either alone or in combination with C. septicum or C. perfringens, can be found in patients with serious underlying disease such as malignancy or acute pancreatitis, with or without neutropenic enterocolitis; the frequency has not been systematically studied. C. tertium may present special problems in terms of both identification and treatment. This organism may stain gram-negative; is aerotolerant; and is resistant to metronidazole, clindamycin, and cephalosporins. Other clostridia from the C. clostridioforme group (including C. clostridioforme, C. hathewayi, and C. bolteae) can cause bacteremia.


InternalMed_Harrison

InternalMed_Harrison. Other clostridia from the C. clostridioforme group (including C. clostridioforme, C. hathewayi, and C. bolteae) can cause bacteremia. The clinical importance of recognizing clostridial bacteremia— especially that due to C. septicum—and starting appropriate treatment immediately (Table 179-1) cannot be overemphasized. Patients with this condition usually are gravely ill, and infection may metastasize to distant anatomic sites, resulting in spontaneous myonecrosis (see next section). Alternative methods to identify bacteremia-causing clostridial species, such as PCR or other rapid diagnostic tests, are not currently available. Anaerobic blood cultures and Gram’s stain interpretation remain the best diagnostic tests at this point. Histotoxic clostridial species such as C. perfringens, C. histolyticum,


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InternalMed_Harrison. Histotoxic clostridial species such as C. perfringens, C. histolyticum, C. septicum, C. novyi, and C. sordellii cause aggressive necrotizing infections of the skin and soft tissues. These infections are attributable in part to the elaboration of bacterial proteases, phospholipases, and cytotoxins. Necrotizing clostridial soft-tissue infections are rapidly progressive and are characterized by marked tissue destruction, gas in the tissues, and shock; they frequently end in death. Severe pain, crepitus, brawny induration with rapid progression to skin sloughing, violaceous bullae, and marked tachycardia are characteristics found in the majority of patients.


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InternalMed_Harrison. Clostridial Myonecrosis (Gas Gangrene) • traumatic gas gangrene C. perfringens myonecrosis (gas gangrene) is one of the most fulminant gram-positive bacterial infections of humans. Even with appropriate antibiotic therapy and management in an intensive care unit, tissue destruction can progress rapidly. Gas gangrene is accompanied by bacteremia, hypotension, and multiorgan failure and is invariably fatal if untreated. Gas gangrene is a true emergency and requires immediate surgical debridement.


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InternalMed_Harrison. The development of gas gangrene requires an anaerobic environment and contamination of a wound with spores or vegetative organisms. Devitalized tissue, foreign bodies, and ischemia reduce locally available oxygen levels and favor outgrowth of vegetative cells and spores. Thus conditions predisposing to traumatic gas gangrene include crush-type injury, laceration of large or medium-sized arteries, and open fractures of long bones that are contaminated with soil or bits of clothing containing the bacterial spores. Gas gangrene of the abdominal wall and flanks follows penetrating injuries such as knife or gunshot wounds that are sufficient to compromise intestinal integrity, with resultant leakage of the bowel contents into the soft tissues. Proximity to fecal sources of bacteria is a risk factor for cases following hip surgery, adrenaline injections into the buttocks, or amputation of the leg for ischemic vascular disease. In the last decade, cutaneous gas gangrene caused by C.


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InternalMed_Harrison. a risk factor for cases following hip surgery, adrenaline injections into the buttocks, or amputation of the leg for ischemic vascular disease. In the last decade, cutaneous gas gangrene caused by C. perfringens, C. novyi, and C. sordellii has been described in the United States and northern Europe among persons injecting black-tar heroin subcutaneously.


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InternalMed_Harrison. The incubation period for traumatic gas gangrene can be as short as 6 h and is usually <4 days. The infection is characterized by the sudden onset of excruciating pain at the affected site and the rapid development of a foul-smelling wound containing a thin serosanguineous discharge and gas bubbles. Brawny edema and induration develop and give way to cutaneous blisters containing bluish to maroon-colored fluid. Such tissue later may become liquefied and slough. The margin between healthy and necrotic tissue often advances several inches per hour despite appropriate antibiotic therapy, and radical amputation remains the single best life-saving intervention. Shock and organ failure frequently accompany gas gangrene; when patients become bacteremic, the mortality rate exceeds 50%.


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InternalMed_Harrison. Diagnosis of traumatic gas gangrene is not difficult because the infection always begins at the site of significant trauma, is associated with gas in the tissue, and is rapidly progressive. Gram’s staining of drainage or tissue biopsy is usually definitive, demonstrating large gram-positive (or gram-variable) rods, an absence of inflammatory cells, and widespread soft-tissue necrosis.


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InternalMed_Harrison. spontaneous (nontraumatic) gas gangrene Spontaneous gas gangrene generally occurs via hematogenous seeding of normal muscle with histotoxic clostridia—principally C. perfringens, C. septicum, and C. novyi and occasionally C. tertium—from a gastrointestinal tract portal of entry (as in colonic malignancy, inflammatory bowel disease, diverticulitis, necrotizing enterocolitis, cecitis, or distal ileitis or after gastrointestinal surgery). These gastrointestinal pathologies permit bacterial access to the bloodstream; consequently, aerotolerant C. septicum can proliferate in normal tissues. Patients surviving bacteremia or spontaneous gangrene due to C. septicum should undergo aggressive diagnostic studies to rule out gastrointestinal pathology.


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InternalMed_Harrison. Additional predisposing host factors include leukemia, lymphoproliferative disorders, cancer chemotherapy, radiation therapy, and AIDS. Cyclic, congenital, or acquired neutropenia also is strongly associated with an increased incidence of spontaneous gas gangrene due to C. septicum; in such cases, necrotizing enterocolitis, cecitis, or distal ileitis is common, particularly among children.


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InternalMed_Harrison. The first symptom of spontaneous gas gangrene may be confusion followed by the abrupt onset of excruciating pain in the absence of trauma. These findings, along with fever, should heighten suspicion of spontaneous gas gangrene. However, because of the lack of an obvious portal of entry, the correct diagnosis is frequently delayed or missed. The infection is characterized by rapid progression of tissue destruction with demonstrable gas in the tissue (Fig. 179-2). Swelling increases, and bullae filled with clear, cloudy, hemorrhagic, or purplish fluid appear. The surrounding skin has a purple hue, which may reflect vascular compromise resulting from the diffusion of bacterial toxins into surrounding tissues. Invasion of healthy tissue rapidly ensues, with quick progression to shock and multiple-organ failure. Mortality rates in this setting range from 67 to 100% among adults; among children, the mortality rate is 59%, with the majority of deaths occurring within 24 h of onset.


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InternalMed_Harrison. patHogenesis of gas gangrene In traumatic gas gangrene, organisms are introduced into devitalized tissue. It is important to recognize that for C. perfringens and C. novyi, trauma must be sufficient to interrupt the blood supply and thereby to establish an optimal anaerobic FIGURE 179-2 Radiograph of patient with spontaneous gas gan-grene due to C. septicum, demonstrating gas in the affected arm and shoulder. environment for growth of these species. These conditions are not strictly required for the more aerotolerant species such as C. septicum and C. tertium, which can seed normal tissues from gastrointestinal lesions. Once introduced into an appropriate niche, the organisms proliferate locally and elaborate exotoxins.


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InternalMed_Harrison. The major C. perfringens extracellular toxins implicated in gas gangrene are α toxin and θ toxin. A lethal hemolysin that has both phospholipase C and sphingomyelinase activities, α toxin has been implicated as the major virulence factor of C. perfringens: immunization of mice with the C-terminal domain of α toxin provides protection against lethal challenge with C. perfringens, and isogenic α toxin–deficient mutant strains of C. perfringens are not lethal in a murine model of gas gangrene. It has been shown in experimental models that the severe pain, rapid progression, marked tissue destruction, and absence of neutrophils in C. perfringens gas gangrene are attributable in large part to α toxin–induced occlusion of blood vessels by heterotypic aggregates of platelets and neutrophils. The formation of these aggregates, which occurs within minutes, is largely mediated by α toxin’s ability to activate the platelet adhesion molecule gpIIb/ IIIa (Fig. 179-3); the implication is that


InternalMed_Harrison

InternalMed_Harrison. The formation of these aggregates, which occurs within minutes, is largely mediated by α toxin’s ability to activate the platelet adhesion molecule gpIIb/ IIIa (Fig. 179-3); the implication is that platelet glycoprotein inhibitors (e.g., eptifibatide, abciximab) may be therapeutic for maintaining tissue blood flow.


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InternalMed_Harrison. C. perfringens θ toxin (perfringolysin) is a member of the thiolactivated cytolysin family known as cholesterol-dependent cytolysins, which includes streptolysin O from group A Streptococcus, pneumolysin from Streptococcus pneumoniae, and several other toxins. Cholesterol-dependent cytolysins bind as oligomers to cholesterol in host cell membranes. At high concentrations, these toxins form ringlike pores resulting in cell lysis. At sublytic concentrations, θ toxin hyperactivates phagocytes and vascular endothelial cells. Cardiovascular collapse and end-organ failure occur late in the course of C. perfringens gas gangrene and are largely attributable to both direct and indirect effects of α and θ toxins. In experimental models, θ toxin causes markedly reduced systemic vascular resistance but increased cardiac output (i.e., “warm shock”), probably via induction of endogenous mediators (e.g., prostacyclin, platelet-activating factor)


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InternalMed_Harrison. FIGURE 179-3 Schematic illustration of the molecular mechanisms of C. perfringens α toxin–induced platelet/neutrophil aggregates. Homotypic aggregates of platelets (not shown) and heterotypic aggregates of platelets and leukocytes are due to α toxin–induced activation of the platelet fibrinogen receptor gpIIb/ IIIa and upregulation of leukocyte CD11b/CD18. Binding of fibrinogen (red) bridges the connection between these adhesion molecules on adjacent cells. An auxiliary role for α toxin–induced upregulation of platelet P-selectin and its binding to leukocyte P-selectin glycoprotein ligand 1 (PSGL-1) or other leukocyte surface carbohydrates also has been demonstrated.


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InternalMed_Harrison. that cause vasodilation. This effect is similar to that observed in gram-negative sepsis. In sharp contrast, α toxin directly suppresses myocardial contractility; the consequence is profound hypotension due to a sudden reduction in cardiac output. The roles of other endogenous mediators, such as cytokines (e.g., tumor necrosis factor, interleukin 1, interleukin 6) and vasodilators (e.g., bradykinin) have not been fully elucidated. C. septicum produces four main toxins—α toxin (lethal, hemolytic, necrotizing activity), β toxin (DNase), γ toxin (hyaluronidase), and Δ toxin (septicolysin, an oxygen-labile hemolysin)—as well as a protease and a neuraminidase. Unlike the α toxin of C. perfringens, that of C. septicum does not possess phospholipase activity. The mechanisms remain to be fully elucidated, but it is likely that each of these toxins contributes uniquely to C. septicum gas gangrene.


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InternalMed_Harrison. Patients with suspected gas gangrene (either traumatic or spontaneous) should undergo prompt surgical inspection of the infected site. Direct examination of a Gram-stained smear of the involved tissues is of major importance. Characteristic histologic findings in clostridial gas gangrene include widespread tissue destruction, a paucity of leukocytes in infected tissues in conjunction with an accumulation of leukocytes in adjacent vessels (Fig. 179-4), and the presence of gram-positive rods (with or without spores). CT and MRI are invaluable for determining whether the infection is localized or is spreading along fascial planes, and needle aspiration or punch biopsy may provide an etiologic diagnosis in at least 20% of cases. However, these techniques should not replace surgical exploration, Gram’s staining, and histopathologic examination. When spontaneous gas gangrene is suspected, blood should be cultured since bacteremia usually precedes cutaneous manifestations by several hours.


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InternalMed_Harrison. For patients with evidence of clostridial gas gangrene, thorough emergent surgical debridement is of extreme importance. All devitalized tissue should be widely resected back to healthy viable muscle and skin so as to remove conditions that allow anaerobic organisms to continue proliferating. Closure of traumatic wounds or compound fractures should be delayed for 5–6 days until it is certain that these sites are free of infection. FIGURE 179-4 Histopathology of experimental gas gangrene due to C. perfringens, demonstrating widespread muscle necrosis, a pau-city of leukocytes in infected tissues, and accumulation of leukocytes in adjacent vessels (arrows). These features are due to the effects of α and θ toxins on muscle cells, platelets, leukocytes, and endothelial cells.


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InternalMed_Harrison. Antibiotic treatment of traumatic or spontaneous gas gangrene (Table 179-1) consists of the administration of penicillin and clindamycin for 10–14 days. Penicillin is recommended on the basis of in vitro sensitivity data; clindamycin is recommended because of its superior efficacy over penicillin in animal models of C. perfringens gas gangrene and in some clinical reports. Controlled clinical trials comparing the efficacy of these agents in humans have not been performed. In the penicillin-allergic patient, clindamycin may be used alone. The superior efficacy of clindamycin is probably due to its ability to inhibit bacterial protein toxin production, its insensitivity to the size of the bacterial load or the stage of bacterial growth, and its ability to modulate the host’s immune response.


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InternalMed_Harrison. C. tertium is resistant to penicillin, cephalosporins, and clindamycin. Appropriate antibiotic therapy for C. tertium infection is vancomycin (1 g every 12 h IV) or metronidazole (500 mg every 8 h IV). The value of adjunctive treatment with hyperbaric oxygen (HBO) for gas gangrene remains controversial. Basic science studies suggest that HBO can inhibit the growth of C. perfringens but not that of the more aerotolerant C. septicum. In vitro, blood and macerated muscle inhibit the bactericidal potential of HBO. Numerous studies in animals demonstrate little efficacy of HBO alone, whereas antibiotics alone—especially those that inhibit bacterial protein synthesis—confer marked benefits. Addition of HBO to the therapeutic regimen provides some additional benefit, but only if surgery and antibiotic administration precede HBO treatment.


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InternalMed_Harrison. In conclusion, gas gangrene is a rapidly progressive infection whose outcome depends on prompt recognition, emergent surgery, and timely administration of antibiotics that inhibit toxin production. Gas gangrene associated with bacteremia probably represents a later stage of illness and is associated with the worst outcomes. Emergent surgical debridement is crucial to ensure survival, and ancillary procedures (e.g., CT or MRI) or transport to HBO units should not delay this intervention. Some trauma centers associated with HBO units may have special expertise in managing these aggressive infections, but proximity and speed of transfer must be carefully weighed against the need for haste.


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InternalMed_Harrison. prognosis of gas gangrene The prognosis for patients with gas gangrene is more favorable when the infection involves an extremity rather than the trunk or visceral organs, since debridement of the latter sites is more difficult. Gas gangrene is most likely to progress to shock and death in patients with associated bacteremia and intravascular hemolysis. Mortality rates are highest for patients in shock at the time of diagnosis. Mortality rates are relatively high among patients with spontaneous gas gangrene, especially that due to C. septicum. Survivors of gas gangrene may undergo multiple debridements and face long periods of hospitalization and rehabilitation.


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InternalMed_Harrison. prevention of gas gangrene Initial aggressive debridement of devitalized tissue can reduce the risk of gas gangrene in contaminated deep wounds. Interventions to be avoided include prolonged application of tourniquets and surgical closure of traumatic wounds; patients with compound fractures are at significant risk for gas gangrene if the wound is closed surgically. Vaccination against α toxin is protective in experimental animal models of C. perfringens gas gangrene but has not been investigated in humans. In addition, as mentioned above, a hyperimmune globulin would represent a significant advance for prophylaxis in victims of acute traumatic injury or for attenuation of the spread of infection in patients with established gas gangrene.


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InternalMed_Harrison. Toxic Shock Syndrome Clostridial infection of the endometrium, particularly that due to C. sordellii, can develop after gynecologic procedures, childbirth, or abortion (spontaneous or elective, surgical or medical) and, once established, proceeds rapidly to TSS and death. Systemic manifestations, including edema, effusions, profound leukocytosis, and hemoconcentration, are followed by the rapid onset of hypotension and multiple-organ failure. Elevation of the hematocrit to 75–80% and leukocytosis of 50,000–200,000 cells/ μL, with a left shift, are characteristic of C. sordellii infection. Pain may not be a prominent feature, and fever is typically absent. In one series, 18% of 45 cases of C. sordellii infection were associated with normal childbirth, 11% with medically induced abortion, and 0.4% with spontaneous abortion; the case-fatality rate was 100% in these groups. Of the infections in this series that were not related to gynecologic procedures or childbirth, 22% occurred in


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InternalMed_Harrison. and 0.4% with spontaneous abortion; the case-fatality rate was 100% in these groups. Of the infections in this series that were not related to gynecologic procedures or childbirth, 22% occurred in injection drug users, and 50% of these patients died. Other infections followed trauma or surgery (42%), mostly in healthy persons, and 53% of these patients died. Overall, the mortality rate was 69% (31 of 45 cases). Of patients who succumbed, 85% died within 2–6 days after infection onset or following procedures.


InternalMed_Harrison

InternalMed_Harrison. Early diagnosis of C. sordellii infections often proves difficult for several reasons. First, the prevalence of these infections is low. Second, the initial symptoms are nonspecific and frankly misleading. Early in the course, the illness resembles any number of infectious diseases, including viral syndromes. Given these vague symptoms and an absence of fever, physicians usually do not aggressively pursue additional diagnostic tests. The absence of local evidence of infection and the lack of fever make early diagnosis of C. sordellii infection particularly problematic in patients who develop deep-seated infection following childbirth, therapeutic abortion, gastrointestinal surgery, or trauma. Such patients are frequently evaluated for pulmonary embolization, gastrointestinal bleeding, pyelonephritis, or cholecystitis. Unfortunately, such delays in diagnosis increase the risk of death, and, as in most necrotizing soft-tissue infections, patients are hypotensive with evidence of organ


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InternalMed_Harrison. or cholecystitis. Unfortunately, such delays in diagnosis increase the risk of death, and, as in most necrotizing soft-tissue infections, patients are hypotensive with evidence of organ dysfunction by the time local signs and symptoms become apparent. In contrast, infection is more readily suspected in injection drug users presenting with local swelling, pain, and redness at injection sites; early recognition probably contributes to the lower mortality rates in this group.


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InternalMed_Harrison. Physicians should suspect C. sordellii infection in patients who present within 2–7 days after injury, surgery, drug injection, childbirth, or abortion and who report pain, nausea, vomiting, and diarrhea but are afebrile. There is little information regarding appropriate treatment for C. sordellii infections. In fact, the interval between onset of symptoms and death is often so short that there is little time to initiate empirical antimicrobial therapy. Indeed, anaerobic cultures of blood and wound aspirates are time-consuming, and many hospital laboratories do not routinely perform antimicrobial sensitivity testing on anaerobes. Antibiotic susceptibility data from older studies suggest that C. sordellii, like most clostridia, is susceptible to β-lactam antibiotics, clindamycin, tetracycline, and chloramphenicol but is resistant to aminoglycosides and sulfonamides. Antibiotics that suppress toxin synthesis (e.g., clindamycin) may possibly prove useful as therapeutic adjuncts since


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InternalMed_Harrison. and chloramphenicol but is resistant to aminoglycosides and sulfonamides. Antibiotics that suppress toxin synthesis (e.g., clindamycin) may possibly prove useful as therapeutic adjuncts since they are effective in necrotizing infections due to other toxin-producing gram-positive organisms.


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InternalMed_Harrison. Other Clostridial Skin and Soft-Tissue Infections Crepitant cellulitis (also called anaerobic cellulitis) occurs principally in diabetic patients and characteristically involves subcutaneous tissues or retroperitoneal tissues, whereas the muscle and fascia are not involved. This infection can progress to fulminant systemic disease. Cases of C. histolyticum infection with cellulitis, abscess forma-995 tion, or endocarditis have also been documented in injection drug users. Endophthalmitis due to C. sordellii or C. perfringens has been described. C. ramosum is also isolated frequently from clinical specimens, including blood and both intraabdominal and soft tissues. This species may be resistant to clindamycin and multiple cephalosporins.


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InternalMed_Harrison. Meningococcal Infections Andrew J. Pollard DEFINITION Infection with Neisseria meningitidis most commonly manifests as asymptomatic colonization in the nasopharynx of healthy adolescents and adults. Invasive disease occurs rarely, usually presenting as either 180 SECTIon 6 bacterial meningitis or meningococcal septicemia. Patients may also present with occult bacteremia, pneumonia, septic arthritis, conjunctivitis, and chronic meningococcemia. N. meningitidis is a gram-negative aerobic diplococcus that colonizes humans only and that causes disease after transmission to a susceptible individual. Several related organisms have been recognized, including the pathogen N. gonorrhoeae and the commensals N. lactamica, N. flavescens, N. mucosa, N. sicca, and N. subflava. N. meningitidis is a catalaseand oxidase-positive organism that utilizes glucose and maltose to produce acid.


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InternalMed_Harrison. Meningococci associated with invasive disease are usually encapsulated with polysaccharide, and the antigenic nature of the capsule determines an organism’s serogroup (Table 180-1). In total, 13 serogroups have been identified (A–D, X–Z, 29E, W, H–J, and L), but just 6 serogroups—A, B, C, X, Y, and W (formerly W135)—account for the majority of cases of invasive disease. Acapsular meningococci are commonly isolated from the nasopharynx in studies of carriage; the lack of capsule often is a result of phase variation of capsule expression, but as many as 16% of isolates lack the genes for capsule synthesis and assembly. These “capsule-null” meningococci and those that express capsules other than A, B, C, X, Y, and W are only rarely associated with invasive disease and are most commonly identified in the nasopharynx of asymptomatic carriers.


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InternalMed_Harrison. Beneath the capsule, meningococci are surrounded by an outer phospholipid membrane containing lipopolysaccharide (LPS, endotoxin) and multiple outer-membrane proteins (Figs. 180-1 and 180-2). Antigenic variability in porins expressed in the outer membrane defines the serotype (PorB) and serosubtype (PorA) of the organism, and structural differences in LPS determine the immunotype. Serologic methods for typing of meningococci are restricted by the limited availability of serologic reagents that can distinguish among the organisms’ highly variable surface proteins. Where available, high-throughput antigen gene sequencing has superseded serology for meningococcal typing. A large database of antigen gene sequences for the outer-membrane proteins PorA, PorB, FetA, Opa, and factor H–binding protein is available online (www.neisseria.org). The number of specialized iron-regulated proteins found in the meningococcal outer membrane (e.g., FetA and transferrin-binding proteins) highlights the


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InternalMed_Harrison. is available online (www.neisseria.org). The number of specialized iron-regulated proteins found in the meningococcal outer membrane (e.g., FetA and transferrin-binding proteins) highlights the organisms’ dependence on iron from human sources. A thin peptidoglycan cell wall separates the outer membrane from the cytoplasmic membrane.


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InternalMed_Harrison. The structure of meningococcal populations involved in local and global spread has been studied with multilocus enzyme electrophoresis (MLEE), which characterizes isolates according to differences in the electrophoretic mobility of cytoplasmic enzymes. However, this technique has mostly been replaced by multi-locus sequence typing (MLST), in which meningococci are characterized by sequence types assigned on the basis of sequences of internal fragments of seven housekeeping genes. The online MLST database currently includes more than 27,000 meningococcal isolates and 10,500 unique sequence types (pubmlst.org/neisseria/). A limited number of hyperinvasive lineages of N. meningitidis have been recognized


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InternalMed_Harrison. FIGURE 180-1 Electron micrograph of Neisseria meningitidis. Black dots are gold-labeled polyclonal antibodies binding surface opacity proteins. Blebs of outer membrane can be seen being released from the bacterial surface (arrow). (Photo courtesy of D. Ferguson, Oxford University.) e.g.FbpA, SodC Periplasmic space e.g.FbpB, FbpC


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InternalMed_Harrison. FIGURE 180-2 Cross-section through surface structures of Neisseria meningitidis. LPS, lipopolysaccharide. (Reprinted with permission from M Sadarangani, AJ Pollard: Lancet Infect Dis 10:112, 2010.) and are responsible for the majority of cases of invasive meningococcal disease worldwide. The apparent genetic stability of these meningococcal clones over decades and during wide geographic spread indicates that they are well adapted to the nasopharyngeal environment of the host and to efficient transmission. While MLST has become established as the main method of genotyping meningococci in many reference laboratories over the past decade, whole-genome sequencing is set to replace this approach in the decade ahead, with almost 1000 genomes already available in the United Kingdom’s national library (www.meningitis.org/genome-library).


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InternalMed_Harrison. The group B meningococcal genome is >2 megabases in length and contains 2158 coding regions. Many genes undergo phase variation that makes it possible to control their expression; this capacity is likely to be important in meningococcal adaptation to the host environment and evasion of the immune response. Meningococci can obtain DNA from their environment and can acquire new genes—including the capsular operon—such that capsule switching from one serogroup to another can occur. Patterns of Disease Up to 500,000 cases of meningococcal disease are thought to occur worldwide each year, and ~10% of the individuals affected die. There are several patterns of disease: epidemic, outbreak (small clusters of cases), hyperendemic, and sporadic or endemic. islands), and the province of Normandy in France.


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InternalMed_Harrison. islands), and the province of Normandy in France. Most countries now experience predominantly sporadic cases (0.3–5 cases per 100,000 population), with many different disease-causing clones involved and usually no clear epidemiologic link between one case and another. The disease rate and the distribution of meningococcal strains vary in different regions of the world and also in any one location over time. For example, in the United States, the rate of meningococcal disease fell from 1.2 cases per 100,000 population in 1997 to <0.15 case per 100,000 in 2012 (Fig. 180-3). Meningococcal disease in the United States was previously dominated by serogroups B and C; however, serogroup Y emerged during the 1990s and became more common than serogroup C in 2007. In contrast, rates of disease in England and Wales rose to >5 cases per 100,000 during the 1990s because of an increase in cases caused by the


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InternalMed_Harrison. ST11 serogroup C clone. As a result of a mass immunization program against serogroup C in 1999, almost all cases in the United Kingdom are now attributed to serogroup B (Fig. 180-4). Over the last decade, most industrialized nations have seen a general decrease in meningococcal disease; this decrease is linked to immunization against serogroup C meningococci in Europe, Canada, and Australia and to adolescent immunization programs for A, C, Y and W in the United States. However, other factors, including changes in population immunity (probably the explanation for the cyclic nature of meningococcal disease rates) as well as a reduction in smoking and passive exposure to tobacco smoke (driven by bans on smoking in buildings and public spaces) across wealthy countries are likely to have contributed to the fall in cases.


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InternalMed_Harrison. Factors Associated with Disease Risk and Susceptibility The principal determinant of disease susceptibility is age, with the peak incidence in the first year of life (Fig. 180-5). The susceptibility of the very young presumably results from an absence of specific adaptive immunity in combination with very close contact with colonized individuals, including parents. Compared with other age groups, infants appear to be particularly susceptible to serogroup B disease: >30% of serogroup B cases in the United States occur during the first year of life. In the early 1.4


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InternalMed_Harrison. Epidemics have continued since the original descriptions of menin gococcal disease, especially affecting the sub-Saharan meningitis belt of Africa, where tens to hundreds of thousands of cases (caused mainly by serogroup A but also by serogroups W and X) may be reported over a season and rates may be as high as 1000 cases per 100,000 popula tion. Serogroup A epidemics took place in Europe and North America after the First and Second World Wars, and serogroup A outbreaks have been documented over the past 30 years in New Zealand, China, Nepal, Mongolia, India, Pakistan, Poland, and Russia. Clusters of cases occur where there is an opportunity for increased transmission—i.e., in (semi-)closed communities such as schools, Cases per 100,000 population 1.2 0.8 0.6 0.4 0.2 colleges, universities, military training centers, and refugee camps.


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InternalMed_Harrison. Cases per 100,000 population 1.2 0.8 0.6 0.4 0.2 colleges, universities, military training centers, and refugee camps. Recently, such clusters have been especially strongly linked with a particular clone (sequence type 11) that is mainly associated with the serogroup C or W capsule but was first described in association Year with serogroup B. Wider and more prolonged community outbreaks FIGURE 180-3 Meningococcal disease in the United States over (hyperendemic disease) due to single clones of serogroup B menin time. ABCs, active bacterial cores. (Adapted from ABC Surveillance data, gococci account for ≥10 cases per 100,000. Regions affected in the Centers for Disease Control and Prevention; www.cdc.gov.) past decade include the U.S. Pacific Northwest, New Zealand (both B,C,YB,CB,C,YBBB,CB,CB,CB,CA,B,CA,B,CB,WB,WAW,AB,CA,W(X)A,W(X)FIGURE 180-4 Global distribution of meningococcal serogroups, 1999–2009.


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InternalMed_Harrison. B,C,YB,CB,C,YBBB,CB,CB,CB,CA,B,CA,B,CB,WB,WAW,AB,CA,W(X)A,W(X)FIGURE 180-4 Global distribution of meningococcal serogroups, 1999–2009. 1990s in North America, the median ages for patients with disease due to serogroups B, C, Y, and W were 6, 17, 24, and 33 years, respectively. After early childhood, a second peak of disease occurs among adolescents and young adults (15–25 years of age) in Europe and North America. It is thought that this peak relates to social behaviors and environmental exposures in this age group, as discussed below. Most cases of infection with N. meningitidis in developed countries today are sporadic, and the rarity of the disease suggests that individual susceptibility may be important. A number of factors probably contribute to individual susceptibility, including the host’s genetic constitution, environment, and contact with a carrier or a case.


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InternalMed_Harrison. The best-documented genetic association with meningococcal disease is complement deficiency, chiefly of the terminal complement components (C5–9), properdin, or factor D; such a deficiency increases the risk of disease by up to 600-fold and may result in recurrent attacks. Complement components are believed to be important for the bactericidal activity of serum, which is considered the principal mechanism of immunity against invasive meningococcal disease. However, when investigated, complement deficiency is found in only a very small proportion of individuals with meningococcal disease (0.3%). Conversely, 7–20% of persons whose disease is caused by the less common serogroups (W, X, Y, Z, 29E) have a complement deficiency. Complement deficiency appears to be associated with serogroup B disease only rarely. Individuals with recurrences of meningococcal disease, particularly those caused by non-B serogroups, should be assessed for complement deficiency by measurement of total hemolytic


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InternalMed_Harrison. only rarely. Individuals with recurrences of meningococcal disease, particularly those caused by non-B serogroups, should be assessed for complement deficiency by measurement of total hemolytic complement activity. There is also limited evidence that hyposplenism (through reduction in phagocytic capacity) and hypogammaglobulinemia (through absence of specific antibody) increase the risk of meningococcal disease. Genetic studies have revealed various associations with disease susceptibility, including complement and mannose-binding lectin deficiency, single-nucleotide polymorphisms in Toll-like receptor (TLR) 4 and complement factor H, and variants of Fc gamma receptors.


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InternalMed_Harrison. Factors that increase the chance of a susceptible individual’s acquiring N. meningitidis via the respiratory route also increase the risk of meningococcal disease. Acquisition occurs through close contact with carriers as a result of overcrowding (e.g., in poor socioeconomic settings, in refugee camps, during the Hajj pilgrimage to Mecca, and during freshman-year residence in college dormitories) and certain social behaviors (e.g., attendance at bars and nightclubs, kissing). Secondary cases may occur in close contacts of an index case (e.g., household members and persons kissing the infected individual); the risk to these contacts may be as high as 1000 times the background rate in the population. Factors that damage the nasopharyngeal epithelium also increase the risk of both colonization with N. meningitidis and invasive disease. The most important of these factors are cigarette smoking (odds ratio, 4.1) and passive exposure to cigarette smoke. In addition, recent viral respiratory


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InternalMed_Harrison. with N. meningitidis and invasive disease. The most important of these factors are cigarette smoking (odds ratio, 4.1) and passive exposure to cigarette smoke. In addition, recent viral respiratory tract infection, infection with Mycoplasma species, and winter or the dry season have been associated with meningococcal disease; all of these factors presumably either increase the expression of adhesion molecules in the nasopharynx, thus


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InternalMed_Harrison. Number of cases FIGURE 180-5 Age distribution of serogroups B and C meningococcal disease in enhancing meningococcal adhesion, or facilitate England and Wales, 1998–1999. (Health Protection Agency, UK; www.hpa.org.uk.) meningococcal invasion of the bloodstream.


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InternalMed_Harrison. N. meningitidis has evolved as an effective colonizer of the human nasopharynx, with asymptomatic infection rates of >25% described in some series of adolescents and young adults and among residents of crowded communities. Point-prevalence studies reveal widely divergent rates of carriage for different types of meningococci. This variation suggests that some types may be adapted to a short duration of carriage with frequent transmission to maintain the population, while others may be less efficiently transmitted but may overcome this disadvantage by colonizing for a long period. Despite the high rates of carriage among adolescents and young adults, only ~10% of adults carry meningococci, and colonization is very rare in early childhood. Many of the same factors that increase the risk of meningococcal disease also increase the risk of carriage, including smoking, crowding, and respiratory viral infection. Colonization of the nasopharynx involves a series of interactions of


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InternalMed_Harrison. risk of meningococcal disease also increase the risk of carriage, including smoking, crowding, and respiratory viral infection. Colonization of the nasopharynx involves a series of interactions of meningococcal adhesins (e.g., Opa proteins and pili) with their ligands on the epithelial mucosa. N. meningitidis produces an IgA1 protease that is likely to reduce interruption of colonization by mucosal IgA.


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InternalMed_Harrison. Colonization should be considered the normal state of meningococcal infection, with an increased risk of invasion being the unfortunate consequence (for both host and organism) of adaptations of hyperinvasive meningococcal lineages. The meningococcal capsule is an important virulence factor: acapsular strains only very rarely cause invasive disease. The capsule provides resistance to phagocytosis and may be important in preventing desiccation during transmission between hosts. Antigenic diversity in surface structures and an ability to vary levels of their expression have probably evolved as important factors in maintaining meningococcal populations within and between individual hosts.


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InternalMed_Harrison. Invasion through the mucosa into the blood occurs rarely, usually within a few days of acquisition of an invasive strain by a susceptible individual. Only occasional cases of prolonged colonization prior to invasion have been documented. Once the organism is in the bloodstream, its growth may be limited if the individual is partially immune, although bacteremia may allow seeding of another site, such as the meninges or the joints. Alternatively, unchecked proliferation may continue, resulting in high bacterial counts in the circulation. During growth, meningococci release blebs of outer membrane (Fig. 180-1) containing outer-membrane proteins and LPS. Endotoxin binds cell-bound CD14 in association with TLR4 to initiate an inflammatory cascade with the release of high levels of various mediators, including tumor necrosis factor (TNF) α, soluble TNF receptor, interleukin (IL) 1, IL-1 receptor antagonist, IL-1β, IL-6, IL-8, IL-10, plasminogenactivator inhibitor 1 (PAI-1), and leukemia


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InternalMed_Harrison. including tumor necrosis factor (TNF) α, soluble TNF receptor, interleukin (IL) 1, IL-1 receptor antagonist, IL-1β, IL-6, IL-8, IL-10, plasminogenactivator inhibitor 1 (PAI-1), and leukemia inhibitory factor. Soluble CD14-bound endotoxin acts as a mediator of endothelial activation. The severity of meningococcal disease is related both to the levels of endotoxin in the blood and to the magnitude of the inflammatory response. The latter is determined to some extent by polymorphisms in the inflammatory response genes (and their inhibitors), and the release of the inflammatory cascade heralds the development of meningococcal septicemia (meningococcemia). Endothelial injury is central to many clinical features of meningococcemia, including increased vascular permeability, pathologic changes in vascular tone, loss of thromboresistance, intravascular coagulation, and myocardial dysfunction. Endothelial injury leads to increased vascular permeability (attributed to loss of glycosaminoglycans


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InternalMed_Harrison. vascular tone, loss of thromboresistance, intravascular coagulation, and myocardial dysfunction. Endothelial injury leads to increased vascular permeability (attributed to loss of glycosaminoglycans and endothelial proteins), with subsequent gross proteinuria. Leakage of fluid and electrolytes into the tissues from capillaries (“capillary leak syndrome”) leads to hypovolemia, tissue edema, and pulmonary edema. Initial compensation results in vasoconstriction and tachycardia, although cardiac output eventually falls. While resuscitation fluids may restore circulating volume, tissue edema will continue to increase, and, in the lung, the consequence may be respiratory failure.


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InternalMed_Harrison. Intravascular thrombosis (caused by activation of procoagulant pathways in association with upregulation of tissue factor on the endothelium) occurs in some patients with meningococcal disease and results in purpura fulminans and infarction of areas of skin or even of whole limbs. At the same time, multiple anticoagulant pathways are downregulated through loss of endothelial thrombomodulin and protein C receptors and decreases in levels of antithrombin III, protein C, protein S, and tissue factor pathway inhibitor. Thrombolysis is also profoundly impaired in meningococcal sepsis through the release of high levels of PAI-1.


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InternalMed_Harrison. Shock in meningococcal septicemia appears to be attributable to a combination of factors, including hypovolemia, which results from the capillary leak syndrome secondary to endothelial injury, and myocardial depression, which is driven by hypovolemia, hypoxia, metabolic derangements (e.g., hypocalcemia), and cytokines (e.g., IL-6). Decreased perfusion of tissues as a result of intravascular thrombosis, vasoconstriction, tissue edema, and reduced cardiac output in meningococcal septicemia can cause widespread organ dysfunction, including renal impairment and—later in the disease—a decreased level of consciousness due to central nervous system involvement.


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InternalMed_Harrison. Bacteria that reach the meninges cause a local inflammatory response—with release of a spectrum of cytokines similar to that seen in septicemia—that presents clinically as meningitis and is thought to determine the severity of neuronal injury. Local endothelial injury may result in cerebral edema and rapid onset of raised intracranial pressure in some cases.


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InternalMed_Harrison. As discussed above, the most common form of infection with N. meningitidis is asymptomatic carriage of the organism in the nasopharynx. Despite the location of infection in the upper airway, meningococcal pharyngitis is rarely reported; however, upper respiratory tract symptoms are common prior to presentation with invasive disease. It is not clear whether these symptoms relate to preceding viral infection (which may promote meningococcal acquisition) or to meningococcal acquisition itself. After acquiring the organism, susceptible individuals develop disease manifestations in 1–10 days (usually <4 days, although colonization for 11 weeks has been documented).


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InternalMed_Harrison. Along the spectrum of presentations of meningococcal disease, the most common clinical syndromes are meningitis and meningococcal septicemia. In fulminant cases, death may occur within hours of the first symptoms. Occult bacteremia is also recognized and, if untreated, progresses in two-thirds of cases to focal infection, including meningitis or septicemia. Meningococcal disease may also present as pneumonia, pyogenic arthritis or osteomyelitis, purulent pericarditis, endophthalmitis, conjunctivitis, primary peritonitis, or (rarely) urethritis. Perhaps because it is difficult to diagnose, pneumococcal pneumonia is not commonly reported but is associated with serogroups Y, W, and Z and appears most often to affect individuals >10 years of age.


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InternalMed_Harrison. Rash A nonblanching rash (petechial or purpuric) develops in >80% of cases of meningococcal disease; however, the rash is often absent early in the illness. Usually initially blanching in nature (macules, maculopapules, or urticaria) and indistinguishable from more common viral rashes, the rash of meningococcal infection becomes petechial or frankly purpuric over the hours after onset. In the most severe cases, large purpuric lesions develop (purpura fulminans). Some patients (including those with overwhelming sepsis) may have no rash. While petechial rash and fever are important signs of meningococcal disease, fewer than 10% of children (and, in some clinical settings, fewer than 1% of patients) with this presentation are found to have meningococcal disease. Most patients presenting with a petechial or purpuric rash have a viral infection (Table 180-2). The skin lesions exhibit widespread endothelial necrosis and occlusion of small vessels in the dermis and subcutaneous tissues, with


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InternalMed_Harrison. a petechial or purpuric rash have a viral infection (Table 180-2). The skin lesions exhibit widespread endothelial necrosis and occlusion of small vessels in the dermis and subcutaneous tissues, with a neutrophilic infiltrate.


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InternalMed_Harrison. Meningitis Meningococcal meningitis commonly presents as nonspecific manifestations, including fever, vomiting, and (especially in infants and young children) irritability, and is indistinguishable from other forms of bacterial meningitis unless there is an associated petechial or purpuric rash, which occurs in two-thirds of cases. Headache is rarely reported in early childhood but is more common in later childhood and adulthood. When headache is present, the following features, in association with fever or a history of fever, are suggestive of bacterial meningitis: neck stiffness, photophobia, decreased CoMMon CAuSES of PETECHIAL oR PuRPuRIC RASHES Deficiency of protein C or S (including postvaricella protein S deficiency) Platelet disorders (e.g., idiopathic thrombocytopenic purpura, drug effects, bone marrow infiltration) Henoch-Schönlein purpura, connective tissue disorders, trauma (including nonaccidental injuries in children)


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InternalMed_Harrison. Henoch-Schönlein purpura, connective tissue disorders, trauma (including nonaccidental injuries in children) Pneumococcal, streptococcal, staphylococcal, or gram-negative bacterial sepsis level of consciousness, seizures or status epilepticus, and focal neurologic signs. Classic signs of meningitis, such as neck stiffness and photophobia, are often absent in infants and young children with bacterial meningitis, who more usually present with fever and irritability and may have a bulging fontanelle.


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InternalMed_Harrison. While 30–50% of patients present with a meningitis syndrome alone, up to 40% of meningitis patients also present with some features of septicemia. Most deaths from meningococcal meningitis alone (i.e., without septicemia) are associated with raised intracranial pressure presenting as a reduced level of consciousness, relative bradycardia and hypertension, focal neurologic signs, abnormal posturing, and signs of brainstem involvement—e.g., unequal, dilated, or poorly reactive pupils; abnormal eye movement; and impaired corneal responses (Chap. 328).


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InternalMed_Harrison. Septicemia Meningococcal septicemia alone accounts for up to 20% of cases of meningococcal disease. The condition may progress from early nonspecific symptoms to death within hours. Mortality rates among children with this syndrome have been high (25–40%), but early aggressive management (as discussed below) may reduce the figure to <10%. Early symptoms are nonspecific and suggest an influenza-like illness with fever, headache, and myalgia accompanied by vomiting and abdominal pain. As discussed above, the rash, if present, may appear to be viral early in the course until petechiae or purpuric lesions develop. Purpura fulminans occurs in severe cases, with multiple large purpuric lesions and signs of peripheral ischemia. Surveys of patients have indicated that limb pain, pallor (including a mottled appearance and cyanosis), and cold hands and feet may be prominent. Shock is manifested by tachycardia, poor peripheral perfusion, tachypnea, and oliguria. Decreased cerebral perfusion


InternalMed_Harrison

InternalMed_Harrison. a mottled appearance and cyanosis), and cold hands and feet may be prominent. Shock is manifested by tachycardia, poor peripheral perfusion, tachypnea, and oliguria. Decreased cerebral perfusion leads to confusion, agitation, or decreased level of consciousness. With progressive shock, multiorgan failure ensues; hypotension is a late sign in children, who more commonly present with compensated shock (tachycardia, poor peripheral perfusion, and normal blood pressure). Poor outcome is associated with an absence of meningism, hypotension, young age, coma, relatively low temperature (<38°C), leukopenia, and thrombocytopenia. Spontaneous hemorrhage (pulmonary, gastric, or cerebral) may result from consumption of coagulation factors and thrombocytopenia.


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InternalMed_Harrison. Chronic Meningococcemia Chronic meningococcemia, which is rarely recognized, presents as repeated episodes of petechial rash associated with fever, joint pain, features of arthritis, and splenomegaly that may progress to acute meningococcal septicemia if untreated. During the relapsing course, bacteremia characteristically clears without treatment and then recurs. The differential diagnosis includes bacterial endocarditis, acute rheumatic fever, Henoch-Schönlein purpura, infectious mononucleosis, disseminated gonococcal infection, and immune-mediated vasculitis. This condition has been associated with complement deficiencies in some cases and with inadequate sulfonamide therapy in others. A study from the Netherlands found that half of isolates from patients with chronic meningococcemia had an underacylated lipid A (part of the surface LPS molecule) due to an lpxL1 gene mutation, which markedly reduces the inflammatory response to 999 endotoxin.


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InternalMed_Harrison. Postmeningococcal Reactive Disease In a small proportion of patients, an immune complex disease develops ~4–10 days after the onset of meningococcal disease, with manifestations that include a maculopapular or vasculitic rash (2% of cases), arthritis (up to 8% of cases), iritis (1%), pericarditis, and/or polyserositis associated with fever. The immune complexes involve meningococcal polysaccharide antigen and result in immunoglobulin and complement deposition with an inflammatory infiltrate. These features resolve spontaneously without sequelae. It is important to recognize this condition since a new onset of fever and rash can lead to concerns about relapse of meningococcal disease and unnecessarily prolonged antibiotic treatment.


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InternalMed_Harrison. Like other invasive bacterial infections, meningococcal disease may produce elevations of the white blood cell (WBC) count and of values for inflammatory markers (e.g., C-reactive protein and procalcitonin levels or the erythrocyte sedimentation rate). Values may be normal or low in rapidly progressive disease, and a lack of rise in these laboratory test values does not exclude the diagnosis. However, in the presence of fever and a petechial rash, these elevations are suggestive of meningococcal disease. In patients with severe meningococcal septicemia, common laboratory findings include hypoglycemia, acidosis, hypokalemia, hypocalcemia, hypomagnesemia, hypophosphatemia, anemia, and coagulopathy.


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InternalMed_Harrison. Although meningococcal disease is often diagnosed on clinical grounds, in suspected meningococcal meningitis or meningococcemia, blood should routinely be sent for culture to confirm the diagnosis and to facilitate public health investigations; blood cultures are positive in up to 75% of cases. Culture media containing sodium polyanethol sulfonate, which may inhibit meningococcal growth, should be avoided. Meningococcal viability is reduced if there is a delay in transport of the specimen to the microbiology laboratory for culture or in plating of cerebrospinal fluid (CSF) samples. In countries where treatment with antibiotics before hospitalization is recommended for meningococcal disease, the majority of clinically suspected cases are culture negative. Real-time polymerase chain reaction (PCR) analysis of whole-blood samples increases the diagnostic yield by >40%, and results obtained with this method may remain positive for several days after administration of antibiotics. Indeed,


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InternalMed_Harrison. (PCR) analysis of whole-blood samples increases the diagnostic yield by >40%, and results obtained with this method may remain positive for several days after administration of antibiotics. Indeed, in the United Kingdom, more than half of clinically suspected cases are currently identified by PCR.


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InternalMed_Harrison. Unless contraindications exist (raised intracranial pressure, uncorrected shock, disordered coagulation, thrombocytopenia, respiratory insufficiency, local infection, ongoing convulsions), lumbar puncture should be undertaken to identify and confirm the etiology of suspected meningococcal meningitis, whose presentation cannot be distinguished from that of meningitis of other bacterial causes. Some authorities have recommended a CT brain scan prior to lumbar puncture because of the risk of cerebral herniation in patients with raised intracranial pressure. However, a normal CT scan is not uncommon in the presence of raised intracranial pressure in meningococcal meningitis, and the decision to perform a lumbar puncture should be made on clinical grounds. CSF features of meningococcal meningitis (elevated protein level and WBC count, decreased glucose level) are indistinguishable from those of other types of bacterial meningitis unless a gram-negative diplococcus is identified. (Gram’s


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InternalMed_Harrison. (elevated protein level and WBC count, decreased glucose level) are indistinguishable from those of other types of bacterial meningitis unless a gram-negative diplococcus is identified. (Gram’s staining is up to 80% sensitive for meningococcal meningitis.) CSF should be submitted for culture (sensitivity, 90%) and (where available) PCR analysis. CSF antigen testing with latex agglutination is insensitive and should be replaced by molecular diagnosis when possible.


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InternalMed_Harrison. Lumbar puncture should generally be avoided in meningococcal septicemia, as positioning for the procedure may critically compromise the patient’s circulation in the context of hypovolemic shock. Delayed lumbar puncture may still be useful when the diagnosis is uncertain, particularly if molecular diagnostic technology is available. In other types of focal infection, culture and PCR analysis of normally sterile body fluids (e.g., synovial fluid) may aid in the diagnosis. Although some authorities have recommended cultures of scrapings 1000 or aspirates from skin lesions, this procedure adds little to the diagnostic yield when compared with a combination of blood culture and PCR analysis. Urinary antigen testing also is insensitive, and serologic testing for meningococcal infection has not been adequately studied. Because N. meningitidis is a component of the normal human nasopharyngeal flora, identification of the organism on throat swabs has no diagnostic value.


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InternalMed_Harrison. Death from meningococcal disease is associated most commonly with hypovolemic shock (meningococcemia) and occasionally with raised intracranial pressure (meningococcal meningitis). Therefore, management should focus on the treatment of these urgent clinical issues in addition to the administration of specific antibiotic therapy. Delayed recognition of meningococcal disease or its associated physiologic derangements, together with inadequate emergency management, is associated with poor outcome. Since the disease is rare, protocols for emergency management have been developed (see www.meningitis.org).


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InternalMed_Harrison. Airway patency may be compromised if the level of consciousness is depressed as a result of shock (impaired cerebral perfusion) or raised intracranial pressure; this situation may require intervention. In meningococcemia, pulmonary edema and pulmonary oligemia (presenting as hypoxia) require oxygen therapy or elective endotracheal intubation. In cases with shock, aggressive fluid resuscitation (with replacement of the circulating volume several times in severe cases) and inotropic support may be necessary to maintain cardiac output. If shock persists after volume resuscitation at 40 mL/kg, the risk of pulmonary edema is high, and elective intubation is recommended to improve oxygenation and decrease the work of breathing. Metabolic derangements, including hypoglycemia, acidosis, hypokalemia, hypocalcemia, hypomagnesemia, hypophosphatemia, anemia, and coagulopathy, should be anticipated and corrected. In the presence of raised intracranial pressure, management includes correction of


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InternalMed_Harrison. hypocalcemia, hypomagnesemia, hypophosphatemia, anemia, and coagulopathy, should be anticipated and corrected. In the presence of raised intracranial pressure, management includes correction of coexistent shock and neurointensive care to maintain cerebral perfusion.


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InternalMed_Harrison. Empirical antibiotic therapy for suspected meningococcal disease consists of a third-generation cephalosporin such as ceftriaxone (75–100 mg/kg per day [maximum, 4 g/d] in one or two divided IV doses) or cefotaxime (200 mg/kg per day [maximum, 8 g/d] in four divided IV doses) to cover the various other (potentially penicillin-resistant) bacteria that may produce an indistinguishable clinical syndrome. Although unusual in most isolates, reduced meningococcal sensitivity to penicillin (a minimal inhibitory concentration of 0.12–1.0 μg/mL) has been reported widely.


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InternalMed_Harrison. Both meningococcal meningitis and meningococcal septicemia are conventionally treated for 7 days, although courses of 3–5 days may be equally effective. Furthermore, a single dose of ceftriaxone or an oily suspension of chloramphenicol has been used successfully in resource-poor settings. No data are available to guide the duration of treatment for meningococcal infection at other foci (e.g., pneumonia, arthritis); antimicrobial therapy is usually continued until clinical and laboratory evidence of infection has resolved. Cultures usually become sterile within 24 h of initiation of appropriate antibiotic chemotherapy.


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InternalMed_Harrison. The use of glucocorticoids for adjunctive treatment of meningococcal meningitis remains controversial since no relevant studies have had sufficient power to determine true efficacy. One large study in adults did indicate a trend toward benefit, and in clinical practice a decision to use glucocorticoids usually must precede a definite microbiologic diagnosis. Therapeutic doses of glucocorticoids are not recommended in meningococcal septicemia, but many intensivists recommend replacement glucocorticoid doses for patients who have refractory shock in association with impaired adrenal gland responsiveness.


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InternalMed_Harrison. Various other adjunctive therapies for meningococcal disease have been considered, but few have been subjected to clinical trials and none can currently be recommended. An antibody to LPS (HA1A) failed to confer a demonstrable benefit. Recombinant bactericidal/permeability-increasing protein (which is not currently available) was tested in a study that had inadequate power to show an effect on mortality rates; however, there were trends toward lower mortality rates among patients who received a complete infusion, and this group also had fewer amputations, fewer blood-product transfusions, and a significantly improved functional outcome. Given that protein C concentrations are reduced in meningococcal disease, the use of activated protein C has been considered since a survival benefit was demonstrated in adult sepsis trials; however, trials in pediatric sepsis (of particular relevance for meningococcal disease) found no benefit and indicated a potential risk of bleeding complications


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InternalMed_Harrison. demonstrated in adult sepsis trials; however, trials in pediatric sepsis (of particular relevance for meningococcal disease) found no benefit and indicated a potential risk of bleeding complications with use of activated protein C.


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InternalMed_Harrison. The postmeningococcal immune-complex inflammatory syndrome has been treated with nonsteroidal anti-inflammatory agents until spontaneous resolution occurs.


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InternalMed_Harrison. About 10% of patients with meningococcal disease die despite the availability of antimicrobial therapy and other intensive medical interventions. The most common complication of meningococcal disease (10% of cases) is scarring after necrosis of purpuric skin lesions, for which skin grafting may be necessary. The lower limbs are most often affected; next in frequency are the upper limbs, the trunk, and the face. On average, 13% of the skin surface area is involved. Amputations are necessary in 1–2% of survivors of meningococcal disease because of a loss of tissue viability after peripheral ischemia or compartment syndromes. Unless there is local infection, amputation should usually be delayed to allow the demarcation between viable and nonviable tissue to become apparent. Approximately 5% of patients with meningococcal disease suffer hearing loss, and 7% have neurologic complications. In one study pain was reported by 21% of survivors, and in a recent analysis of serogroup B


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InternalMed_Harrison. 5% of patients with meningococcal disease suffer hearing loss, and 7% have neurologic complications. In one study pain was reported by 21% of survivors, and in a recent analysis of serogroup B meningococcal disease (the MOSAIC study) as many as one-quarter of survivors had psychological disorders. In some investigations, the rate of complications is higher for serogroup C disease (mostly associated with the ST11 clone) than for serogroup B disease. In patients with severe hypovolemic shock, renal perfusion may be impaired and prerenal failure is common, but permanent renal replacement therapy is rarely needed.


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InternalMed_Harrison. Several studies suggest adverse psychosocial outcomes after meningococcal disease, with reduced quality of life, lowered self-esteem, and poorer neurologic development, including increased rates of attention deficit/hyperactivity disorder and special educational needs. Other studies have not found evidence of such outcomes.


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InternalMed_Harrison. Several prognostic scoring systems have been developed to identify patients with meningococcal disease who are least likely to survive. Factors associated with a poorer prognosis are shock; young age (infancy), old age, and adolescence; coma; purpura fulminans; disseminated intravascular coagulation; thrombocytopenia; leukopenia; absence of meningitis; metabolic acidosis; low plasma concentrations of antithrombin and proteins S and C; high blood levels of PAI-1; and a low erythrocyte sedimentation rate or C-reactive protein level. The Glasgow Meningococcal Septicaemia Prognostic Score (GMSPS) is probably the best-performing scoring system studied so far and may be clinically useful for severity assessment in meningococcal disease. However, scoring systems do not direct the clinician to specific interventions, and the priority in management should be recognition of compromised airways, breathing, or circulation and direct, urgent intervention. Most patients improve rapidly with


InternalMed_Harrison

InternalMed_Harrison. to specific interventions, and the priority in management should be recognition of compromised airways, breathing, or circulation and direct, urgent intervention. Most patients improve rapidly with appropriate antibiotics and supportive therapy. Fulminant meningococcemia is more likely to result in death or ischemic skin loss than is meningitis; optimal emergency management may reduce mortality rates among the most severely affected patients.


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InternalMed_Harrison. Since mortality rates in meningococcal disease remain high despite improvements in intensive care management, immunization is the only rational approach to prevention at a population level. Secondary cases are common among household and “kissing” contacts of cases, and secondary prophylaxis with antibiotic therapy is widely recommended for these contacts (see below).


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InternalMed_Harrison. Polysaccharide Vaccines Purified meningococcal capsular polysaccharide has been used for immunization since the 1960s. Meningococcal polysaccharide vaccines are currently formulated as either bivalent (serogroups A and C) or quadrivalent (serogroups A, C, Y, and W), with 50 μg of each polysaccharide per dose. Local reactions (erythema, induration, and tenderness) may occur in up to 40% of vaccinees, but serious adverse events (including febrile convulsions in young children) are very rarely reported. In adults, the vaccines are immunogenic, but immunity appears to be relatively short-lived (with antibody levels above baseline for only 2–10 years), and booster doses do not induce a further rise in antibody concentration. Indeed, a state of immunologic hyporesponsiveness has been widely reported to follow booster doses of plain polysaccharide vaccines. The repeating units of these vaccines cross-link B cell receptors to drive specific memory B cells to become plasma cells and produce


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InternalMed_Harrison. to follow booster doses of plain polysaccharide vaccines. The repeating units of these vaccines cross-link B cell receptors to drive specific memory B cells to become plasma cells and produce antibody. Because meningococcal polysaccharides are T cell–independent antigens, no memory B cells are produced after immunization, and the memory B-cell pool is depleted such that fewer polysaccharide-specific cells are available to respond to a subsequent dose of vaccine (Fig. 180-6). The clinical relevance of hyporesponsiveness is unknown. Plain polysaccharide vaccines generally are not immunogenic in early childhood, pos-1001 sibly because marginal-zone B cells are involved in polysaccharide responses and maturation of the splenic marginal zone is not complete until 18 months to 2 years of age. The efficacy of the meningococcal serogroup C component is >90% in young adults; no efficacy data are available for the serogroup Y and W polysaccharides in this age group.


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InternalMed_Harrison. Group A meningococcal polysaccharides are exceptional in that they have been found to be effective in preventing disease at all ages. Two doses administered 2–3 months apart to children 3–18 months of age or a single dose administered to older children or adults has a protective efficacy rate of >95%. The vaccine has been widely used in the control of meningococcal disease in the African meningitis belt. The duration of protection appears to be only 3–5 years. There is no meningococcal serogroup B plain polysaccharide vaccine because α-2,8-N-acetylneuraminic acid is expressed on the surface of neural cells in the fetus such that the B polysaccharide is perceived as “self” and therefore is not immunogenic in humans.


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InternalMed_Harrison. Conjugate Vaccines The poor immunogenicity of plain polysaccharide vaccines in infancy has been overcome by chemical conjugation of the polysaccharides to a carrier protein (CRM197, tetanus toxoid, or diphtheria toxoid). Conjugates that contain monovalent serogroup C polysaccharide and quadrivalent vaccines with A, C, Y, and W polysaccharides have been developed, as have vaccines including various other antigen combinations (e.g., tetanus conjugates with serogroup C