1. EPIDEMIOLOGY Infection with H. pylori causes what is perhaps the most prevalent disease in the world. The organism is found in the stomachs of 30 to 50% of adults in developed countries and it is almost universal in developing countries. Colonization increases progressively with age, and children are believed to be the major amplifiers of H. pylori in human populations.

2. PATHOGENESIS H. pylori causes peptic ulcer and gastric cancer In order to persist in the hostile environs of the stomach, H. pylori employs multiple mechanisms to adhere to the gastric mucosa and survive the acid milieu of the stomach. Motility provided by the flagella allows the organisms to swim to the less acid pH locale beneath the gastric mucus, where the urease further creates a more neutral microenvironment by ammonia production. At the mucosa, adherence is mediated by surface proteins, one of which binds to Lewis blood group antigens, often present on the surface of gastric epithelial cells. H. pylori colonization is virtually always accompanied by a cellular infiltrate ranging from minimal mononuclear infiltration of the lamina propria to extensive inflammation with neutrophils, lymphocytes, and microabscess formation. This inflammation may be due to toxic effects of the urease or the VacA. The Cag protein may contribute by stimulation of cytokines (interleukin-8), and a neutrophil-activating protein (NAP) has been shown to recruit neutrophils to the gastric mucosa. Added together urease, Cag, and NAP provide ample explanation for the gastritis that is universal in H. pylori infection.

3. A prolonged and aggressive inflammatory response could lead to epithelial cell death and ulcers, but other virulence factors play a more direct role. The chief of these is VacA, which is responsible for much of the epithelial cell erosion seen in human infection. The vacuolar degeneration it induces is readily visible histologically in gastric biopsies (Fig 22–2). That decades of inflammation and assault by the virulence factors described above could eventually lead to cancer seems logical, but the specific mechanisms of carcinogenesis are unknown. Cag is a leading candidate. A curious paradox is that while Cag strains are associated with ulcers and adenocarcinoma of the lower stomach, they are associated with a decreased incidence of adenocarcinoma of the upper stomach (cardia) and esophagus.

5. Diagnosis The most sensitive means of diagnosis is endoscopic examination, with biopsy and culture of the gastric mucosa. The H. pylori urease is so potent its activity can be directly demonstrated in biopsies in less than an hour. Noninvasive methods include serology and a urea breath test. For the breath test, the patient ingests 13C- or 14C-labeled urea, from which the urease in the stomach produces products that appear as labeled CO2 in the breath. A number of methods for detection of antibody directed against H. pylori are now available.

6. TREATMENT AND PREVENTION H. pylori is susceptible to a wide variety of antimicrobial agents. Bismuth salts (eg, Pepto- Bismol), which in the past were believed to act by coating the stomach, also have antimicrobial activity. Cure rates approaching 95% have been achieved with various combinations of bismuth salts and two antibiotics. Metronidazole, tetracycline, clarithromycin, and amoxicillin have been effective.

7. Epiglotittis

8. H. i n f l u e n z a e D I S E A S E Haemophilus are among the smallest of bacteria. The curved ends of the short (1.0 to 1.5 m) bacilli makes many appear nearly round, hence the term coccobacilli. Hib produces acute, life-threatening infections of the central nervous system, epiglottis, and soft tissues, primarily in children. Disease begins with fever and lethargy, and in the case of acute meningitis, can progress to coma and death in less than 1 day. In affluent countries, Hib disease has been controlled by immunization.

9. EPIDEMIOLOGY H. influenzae can be found in the normal nasopharyngeal flora of 20 to 80% of healthy persons, depending on age, season, and other factors. Prior to the introduction of effective vaccines, approximately 1 in every 200 children developed invasive Hib disease by the age of 5 years. Meningitis is the most common form and most often attacks those under 2 years of age. Cases of epiglottitis and pneumonia tend to peak in the 2- to 5-year age range. Over 90% of these cases are due to the single serotype, Hib.

10. PATHOGENESIS Invasive Disease For unknown reasons, H. influenzae strains commonly found in the normal flora of the nasopharynx occasionally invade into deeper tissues. Bacteremia then leads to spread to the central nervous system and metastatic infections at distant sites such as bones and joints. These events seem to take place within a short period (3 days) after an encounter with a new virulent strain. Systemic spread is typical only for capsulated H. influenzae strains, and over 90% of invasive strains are type b. Attachment to respiratory epithelial cells is mediated by pili and other adhesins. H. influenzae can be seen to invade between the cells of the respiratory epithelium, and for a time resides between and below them. Once past the mucosal barrier, the antiphagocytic capsule confers resistance to Endotoxin in the cell wall is toxic to ciliated respiratory cells, but endotoxemia is not a prominent feature of Haemophilus infection to the extent that it is with N. meningitidis. H. influenzae produces no known exotoxins.

11. Meningitis Meningitis is often preceded by signs and symptoms of an upper respiratory infection, such as pharyngitis, sinusitis or otitis media.

12. Acute Epiglottitis Acute epiglottitis is a dramatic infection in which the inflamed epiglottis and surrounding tissues obstruct the airway. Hib is one of a number of causes. The hallmark of the disease is an inflamed, swollen, cherry-red epiglottis that protrudes into the airway.

14. DIAGNOSIS The combination of clinical findings and a typical Gram smear is usually sufficient to make a presumptive diagnosis of Haemophilus infection. The tiny cells are usually of uniform shape except in cerebrospinal fluid, where some may be elongated to several times their usual length. Confirmation and speciation depends on demonstration of the requirement for X and V factors and/or biochemical tests. Serotyping isunnecessary for clinical purposes but important in epidemiologic and vaccine studies.

15. TREATMENT H. influenzae is often susceptible in vitro to ampicillin and amoxicillin, and usually susceptible to the newer cephalosporins, tetracycline, aminoglycosides, and sulfonamides.

17. PREVENTION Purified PRP vaccines became available in 1985; however, due to the typically poor immune response of infants to polysaccharide antigens, their use was limited to children 24 months of age and older. Because immunization at this age misses the group most susceptible to Hib invasive disease, a new vaccine strategy was needed that included improved stimulation of T cell–dependent immune responses in infants. To achieve this, three PRP-protein conjugate vaccines were developed using proteins derived from Corynebacterium diphtheriae (toxoid, CRM 197) or N. meningitidis (outer membrane protein).

18. Figure