Symposium on Infectious Diseases

Hemophilus Influenzae Infections in Adults Carl W. Norden, M.D. *

Hemophilus injluenzae, a gram-negative pleomorphic rod, is best known as the most common cause of meningitis in children under the age of three years.12 Its recognition as a pathogen for adults has come more recently, but it is now clear that H. injluenzae may be the etiologic agent in adults afflicted with pneumonia, bronchitis, meningitis, epiglottitis, septic arthritis, pericarditis, and endocarditis.

Microbiology and Epidemiology The hemophilus group consists of pleomorphic gram-negative, aerobic, nonmotile bacilli with enzyme systems inadequate to support growth in unenriched media. H. injluenzae requires both factor V (heat labile DPN or TPN) and factor X (derived from blood pigment and heat stable) for optimal growth. H. parainjluenzae differs in that it requires only V factor. Some workers feel that H. parainjluenzae represents one end of a series of H. injluenzae strains, and that there is little point in distinguishing it from H. injluenzae. 43 Pittman's observation, that a minority of strains of H. injluenzae differed from the majority found in that respiratory tract by the possession of capsules, has enhanced our understanding of this organism. 35 The capsulated strains, of which there are six antigenically distinct types (a-f) are responsible for most severe acute pyogenic infections by this organism; the role of noncapsulated (nontypable) strains in production of disease is less clear. Type b, which is associated with most cases of meningitis and epiglottitis, is the only capsulated H. injluenzae containing a pentose as the sugar component of its capsule; the other capsulated types contain a hexose. Type b, therefore appears to be unique among hemophilus strains not only in its relative virulence for man, but also in the chemical nature of its capsular substance. Most of our knowledge of the epidemiology of H. injluenzae comes from studies of children rather than adults. Man is the only natural *Professor of Medicine, University of Pittsburgh School of Medicine; Head, Infectious Diseases Unit, Moritefiore Hospital, Pittsburgh, Pennsylvania

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host for H. injiuenzae. Noncapsulated strains are commonly found in the upper respiratory tract of healthy individuals, while capsulated strains are found far less commonly (usually in less than 6 per cent of individuals studied).43 Rates of recovery of H. injiuenzae from older children and adults are generally lower than that from healthy younger children. 43 Carriage rates also vary widely with geographic 10cation. 43 The duration of carriage is unclear, but H. injiuenzae may be present intermittently or may persist for months. 43 Very little information is available about carriage of this organism in other parts of the body. Host Defense Mechanisms The age-related pattern of illness caused by Hemophilus injiuenzae, type b, has usually been explained by the presence or absence of bactericidal antibodies to this organism. Meningitis from H. injiuenzae is rare in the newborn infant, most prevelant between ages 3 months to 3 years, and then gradually declines in frequency so that it is uncommon in adults. 30 Fothergill and Wright(1933) showed an inverse relationship between the presence of bactericidal antibodies (ability of the blood to kill H. injiuenzae, type b in the presence of complement) and meningitis in that such antibodies were found at birth, declined abruptly at about 2 months, and remained infrequent until about 3 years of age. 16 The blood of an increasing proportion of older children acquired bactericidal antibodies such that after age 10 all individuals tested had these antibodies. Thus, to explain the findings of pyogenic infection with H. injiuenzae, type b, in adults, earlier reports have stressed the frequent coexistence of conditions which could impair host defense mechanisms, such as alc{)holism, diabetes, or deficient immunogloblulins. 24 The proliferation of recent articles dealing with the immunology of infection with H. injiuenzae, type b has made it clear that the simple inverse relationship between bactericidal antibodies and susceptibility to H. injiuenzae, type b infections, postulated by Fothergill 44 years ago, is open to doubt. Several surveys of the prevalence of bactericidal antibodies in healthy populations have given conflicting results (many of these differences may be explained by technical factors).3. 15. 18. 19.32 More sensitive radioimmunoassays for anti-capsular H. injiuenzae, type b antibodies have been developed, but there are still no hard data as to what level of these antibodies is protective against H emophilus injiuenzae, type b disease. The role of opsonizing antibodies against H. injiuenzae, type b in host defense mechanisms is also unclear. Robbins and his co-workers have demonstrated that organisms such as E. coli which share common antigenic structures with the capsule of H. injiuenzae, type.b can, if fed to animals or human beings, stimulate the formation of antibodies to Hemophilus injiuenzae, type b. 38 This observation may explain the development of antibodies to H. injiuenzae, type b in the normal population since only a small segment of that population will carry H. injiuenzae, type b at any time in their lives. Finally, the genetic constitution of the host may also be impor-

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taut in susceptibility to infection with H. influenzae type b. Whisnant et al. have demonstrated differences in both MNS phenotype and HLA antigen frequencies in individuals with Hemophilus influenzae, type b meningitis when compared with patients with H. influenzae, type b epiglottitis or normal controls.45 Immunization

Intense investigative efforts on the immunology of polysaccharide encapsulated organisms have resulted in the licensing of meningococcal types A and C vaccines; a dodecavalent vaccine against the most common types of pneumococci has been released. Vaccines derived from the polysaccharide capsular material of H. influenzae, type bare available, under investigational drug status. Such vaccines have been demonstrated, in clinical trials, to be safe and to produce satisfactory antibody responses in one trial in individuals over 18 months of age and in another in children over 3 years of age. 29,34 Unfortunately, the failure to produce a satisfactory immunologic response in children under 18 months of age, the target population most at risk for serious infections with this organism, limits the value of these vaccines. Further efforts to develop effective means of immunizing against infection with H. influenzae, type b are in progress; it seems likely that the relationship between antibodies and immunity to H. influenzae, type b disease will be clarified as these investigations continue.

DISEASE STATES Pneumonia and Bronchitis

The importance of H. influenzae as a pathogen in respiratory tract infections has been the subject of much study. For convenience, it is easiest to consider those cases in which the organism is isolated from the blood and compare it with those cases without bacteremia. In the bacteremic form of H. influenzae pneumonia, the great majority of strains isolated from the blood are generally capsulated and predominantly type b. 27 , 36 The clinical presentation in these patients closely resembles pneumococcal pneumonia. In both, the pneumonia tends to be lobar or segmental and may be complicated by the development of sterile or infected pleural effusions. Patients with the bacteremic form of H. influenzae pneumonia may also present with a diffuse bronchopneumonia. Many of the patients who develop this form of pneumonia have underlying chronic lung disease or alcoholism, but this illness can also present in normal individuals. Treatment includes appropriate antibiotic therapy and drainage of pleural effusions if clinically significant. Mortality may be high, owing to the advanced age of these patients and chronic underlying illnesses. The significance of H. influenzae in the nonbacteremic forms of respiratory infection has been questiioned, but recent studies support its role as a pathogen. Everett et al. reported 18 patients with pneumonia from whom H. influenzae was isolated in pure culture from trans-

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tracheal aspirates. 12 In only one patient was a positive culture of blood obtained; Hemophilus influenzae, type b was recovered. Serotyping was attempted in four other isolates; all were nontypable. The clinical picture was as described for the bacteremic form and was indistinguishable from other bacterial pneumonias. Somewhat weaker evidence for H. influenzae being the cause of pneumonia in adults is provided by Douglas, who studied 632 Melanesians with a clinical diagnosis of pneumonia. 8 Of 55 patients with positive blood cultures, only 2 grew H. influenzae while 51 grew pneumococcus. H. influenzae was cultured from 44 per cent of sputum specimens, and it was the only pathogen grown from sputum in 18 per cent of patients. In a comparable population without evidence of pneumonia, the rate for isolation of H. influenzae from sputum was 8 per cent. Although difficult to prove, it seems likely that noncapsulated strains of H. influenzae can multiply in the alveoli and lead to pulmonary exudation and consolidation. Because of their low invasive capacity, bacteremia is rare with these organisms. The pathogenicity of H. influenzae for the alveoli may be enhanced in populations whose respiratory defense mechanisms are previously impaired. Turk and May have extensively reviewed the evidence for the pathogenicity of H. influenzae in the bronchi. 43 H. influenzae (generally noncapsulated) was isolated significantly more frequently from individuals with chronic bronchitis producing purulent sputum than from similar patients with mucoid sputum. Further, May showed that pus disappeared from the sputum when H. influenzae (together with various other organisms) was eliminated by antibiotic therapy; subsequent relapse was associated with the reappearance in the sputum of H. influenzae, but not of other possible pathogens. 43 Smith et al. 41 studied the importance of noncapsulated strains of H. influenzae and H. parainfluenzae in the pathogenesis of chronic obstructive pulmonary disease. H. influenzae was isolated more often from sputum cultures from patients with severe chronic obstructive pulmonary disease (14 per cent) than from patients with mild disease (5 per cent) whereas H. parainfluenzae was isolated with equal frequency from these two groups. H. influenzae was present in the sputum more often during exacerbations of acute respiratory illness (15 per cent) than during symptom-free periods (10 per cent), while rates of isolation of H. parainfluenzae were not different during illness. Rises in antibody titer to H. influenzae were detected and in over half the cases were associated with acute respiratory illnesses; no rises in antibody titer were detected with H. parainfluenzae. These data suggest that noncapsulated strains of H. influenzae may have pathogenic potential in patients with chronic obstructive pulmonary disease. Smith et al. also observed that viral infections in patients with chronic obstructive pulmonary disease are associated with increased rates of isolation of H. influenzae and that invasion of H. influenzae, as judged by seroconversion, may also be a sequela of viral infection. To summarize my own feelings, there is no question of the signifi-

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cance of H. injtuenzae as a pathogen when it is isolated from either blood or a transtracheal aspiration from a patient with pneumonia. In patients with an acute exacerbation of chronic bronchitis, who are producing purulent sputum, H. injtuenzae should be regarded as a likely pathogen and treated if it is recovered on cultures of sputum or transtracheal aspirate. The response (or lack of response) to chemotherapy in such individuals is probably the best proof the best proof of pathogenicity for this organism.

Meningitis The great majority of patients with H. injtuenzae, type b meningitis are under 3 years of age. However, in any adult presenting with a clinical picture of meningitis, Hemophilus injtuenzae, type b must be considered as a possible etiologic agent. The clinical presentation of Hemophilus injtuenzae, type b meningitis is no different from that due to the pneumococcus. 13 The spinal fluid must be carefully subjected to gram stain since, unless adequately decolorized, the purple granules found in the organism may create the impression of gram-positive cocci and result in an error in diagnosis. 33 In adult patients with H. injtuenzae, type b meningitis, underlying conditions such as cerebrospinal fluid rhinorrhea, diabetes mellitus, immune deficiencies, and alcoholism should be sought. A predisposing cause is frequently not found, and it is clear that H. injtuenzae meningitis can affect normal hosts. The prognosis for complete recovery is good with antibiotic therapy. Epiglottitis Hemophilus injtuenzae, type b is the most common cause of acute epiglottitis in adults; the etiologic diagnosis is usually made by culture of blood. 5,17,21 Acute epiglottitis is a disease characterized by rapid progression of sore throat, dysphagia, and upper airway obstruction. Although it is a disease affecting primarily children from 1 to 5 years old, it also occurs in adults. The onset of symptoms may be acute (as short as 2 to 3 hours), manifesting as great difficulty in breathing and swallowing. Uniformly, the epiglottis is greatly swollen and cherry red. The onset may be more insidious, with sore throat and hoarseness for several days before the appearance of acute symptoms. Acute epiglottitis is a true emergency; the urgency of correct diagnosis and appropriate therapy to prevent fatalities cannot be overemphasized. The diagnosis can be made rapidly by indirect mirror laryngoscopic examination. Lateral roentgenograms of the neck may show edema of the epiglottis and narrowing of the glottic aperture, but such x-rays are rarely essential for making the diagnosis and appropriate therapy should not be delayed in order to do such studies. The key to successful treatment is the establishment of an adequate airway; tracheostomy is usually indicated although in milder cases treatment with steroids and antibiotics has been successful. In the acute fuhninant form in adults, tracheostomy is still the procedure of choice.

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Septic Arthritis

Hemophilus injiuenzae, type b is a relatively infrequent cause of septic arthritis in adults. 26, 37 In the majority of cases reported in the literature, patients with Hemophilus injiuenzae, type b suppurative arthritis had histories of either trauma to the infected joint, diabetes mellitus, alcohol intake, or rheumatoid arthritis. The specific diagnosis is made by culture of the joint fluid and/or the blood. Treatment is the same as for any other form of septic arthritis, i.e., aspiration and systemic antibiotic therapy. Pericarditis

Hemophilus injiuenzae, type b has been reported infrequently as a cause of purulent pericarditis in adults. 2, 7, 9 Patients frequently have an antecedent history of a severe upper respiratory infection, and it is presumed that septicemia occurs with subsequent infection of the pericardium. The symptoms are those of both acute systemic infection and of acute hemodynamic embarrassment secondary to cardiac tamponade. The treatment of H. injiuenzue pericarditis, as with other forms of purulent pericarditis, consists of adequate surgical drainage and appropriate antimicrobial therapy. Endocarditis Two excellent reviews of endocarditis due to H. injiuenzae and H. parainjiuenzae have recently appeared. 6, 28 A review of 35 cases of H. parainjiuenzae endocarditis reported the median age of patients to be 27 years with females predominating, a reversal of the usual ratio for all endocarditis which is two to one with males predominating. Endocarditis due to H. parainjiuenzae involved the same valves as subacut~ endocarditis in general. One striking feature of H. parainjiuenzae endocarditis is the occurrence of major arterial emboli. Arterial emboli were noted in 57 per cent of cases, whereas in subacute endocarditis in general, the incidence of arterial emboli approximates 20 per cent. Major arterial occlusion from emboli in H. parainjiuenzae endocarditis is similar to that seen in fungal endocarditis. In each, embolic occlusion of major arteries is due to large friable vegetations. It is possible that the pathogenetic mechanisms may be similar since microscopic evaluation of resected emboli in H. parainjiuenzae endocarditis reveals the organisms growing in long mat-like chains, bearing a striking resemblance to the long branching hyphae and pseudohyphae seen with such fungi as Aspergillus or Candida. 6 Only 5 cases of endocarditis due to H. injiuenzae have been described in adults.28 All 5 patients were known to have valvular heart disease and the course was subacute with long prodromal periods. None of the 5 had major arterial emboli; 3 of 5 recovered with appropriate antibiotic therapy. The diagnosis of bacterial endocarditis due to H. parainjiuenzae or H. injiuenzae requires positive blood cultures in association with an appropriate clinical picture. Positive blood cultures may be difficult to obtain because of the fastidious requirements of the organisms. The organism can be isolated from aerobic cultures; routine subculturing

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to supplemented chocolate agar and incubation in an enhanced carbon dioxide environment should increase the yield. The initial culture media used must contain a source of X and V factors. Genital and Urinary Tract Infections H. injiuenzae has occasionally been reported as a cause of genital tract infections. 10, 14 There are case reports of salpingitis with abscesses in the Fallopian tubes from which H. injiuenzae has been recovered. H. injiuenzae has also been the etiologic agent in postpartum bacteremia with the source being either endometritis or purulent amnionitis. H. injiuenzae may be part of the normal vaginal flora, and this is the most likely source of infection in the genital tract. Urinary tract infection from H. injiuenzae is quite rare. 1, 4 In general, the strains recovered from the urinary tract are noncapsulated and are found in association with underlying diseases of the urinary tract such as calculi, congenital abnormalities, or trauma. If H. injiuenzae is the only organism isolated repeatedly from the urine of patients with clinical urinary tract infection, appropriate antimicrobial therapy should be instituted. Cholecystitis H. injiuenzae has rarely been associated with infection of the gallbladder. Keefer and Rammelkamp reported a case of H. injiuenzae bacteremia (nontypable strain) in a patient with recurrent fever. 25 Removal of the gallbladder which revealed cholecystitis and cholelithiasis (but was not cultured) produced a complete recovery. More recently, a case of cholecystitis in which H. injiuenzae (nontypable) was the only pathogen recovered from the inflamed gallbladder wall was reported. 40 Post-Splenectomy Infections in Adults Adult patients with splenectomy for trauma or as part of staging for Hodgkin's disease have been reported to be susceptible to overwhelming infections. 31 The usual etiologic agents in these instances are the trio of polysaccharide encapsulated organisms, the pneumococcus, the meningococcus, and H. injiuenzae, type b. The exact reasons for the susceptibility of splenectomized individuals to such overwhelming infection are not known, and may not always be explained on the basis of splenectomy alone. Recently, it was shown that among individuals with Hodgkin's disease, the only group with low levels of antibodies to H. injiuenzae, type b were patients who had received both radiotherapy and chemotherapy.44 The presence or absence of the spleen in this group of patients had no effect on H. injiuenzae antibody titers. The potential role for a vaccine against H. injiuenzae, type b (and also against the common types of pneumococcus and meningococcus) in adult patients who have undergone splenectomy is not yet defined. Clinical trials of available vaccines with monitoring of antibody levels would seem appropriate. Presently, if presented with a splenectomized patient with overwhehning infection, appropriate antiInicrobial therapy must cover H. injiuenzae as well as pneumococci and meningococci.

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Diagnosis of Infection The diagnosis of infections due to H. injluenzae depends to some extent on the enthusiasm and experience with which a bacteriologist approaches this task. Obviously, the laboratory requires adequately obtained samples of cerebrospinal fluid, blood, sputum, and so forth. Such specimens must then be placed in primary media which can support the growth of H. injluenzae; rabbit blood agar will support such growth, but sheep blood agar will not. Subcultures to supplemented chocolate agar should be done and suspicious organisms should be identified and typed with appropriate anti-serum, if they are capsulated. A sensitive supplement to standard bacteriologic techniques for the diagnosis of infections caused by H. injluenzae, type b is the use of countercurrent immunoelectrophoresis (CIE).20 This technique can be used to detect the capsular antigen of H. injluenzae, type b in body fluids of patients with systemic diseases caused by that organism. This may be particularly useful in the diagnosis of partially treated bacterial meningitis where the organism may not be recovered by culture, but antigen may still be detected by countercurrent immunoelectrophoresis. Antibiotic Sensitivity and Therapy Until March, 1974, it could be safely said that for infections with H. injluenzae, antibiotic susceptibility testing need not be done since resistance of H. injluenzae to the commonly used agents, ampicillin and chloramphenicol, had not been reported. That degree of security was stripped away when the CDC Morbidity and Mortality Weekly Report of March 2, 1974, described two cases of meningitis caused by ampicillin-resistant H. injluenzae, type b. Since that initial disquieting report, the frequency of isolations of ampicillin-resistant H. injluenzae, type b has steadily increased. The mechanism of resistance is due to the production of beta-Iactamase. Because resistance of H. injluenzae to ampicillin appears to be mediated solely by betalactamase production, tests to determine if the organism produces this enzyme have been devised which are more rapid and easier to perform than standard susceptibility tests. 22 , 23, 42 Ampicillin-resistant H. injluenzae, type b strains appear to be equally virulent and as capable of spread to contacts as ampicillin-sensitive strains. 39 To date, all ampicillin-resistant strains of H. injluenzae, type b have been reported as sensitive to chloramphenicol. In the Morbidity and Mortality Weekly Report of December 10, 1976, H. injluenzae, type b resistant to chloramphenicol, but sensitive to ampicillin was reported to have been recovered from the blood and cerebrospinal fluid of a 9 month old child. Other agents which may be effective against ampicillin-resistant H. injluenzae are tetracyclines and trimethoprimsulfamethoxazole. Among investigational drugs, some of the newer cephalosporins have good activity against H. injluenzae. ll , 23 How then should one approach a patient with systemic infection caused by H. injluenzae? In the case of meningitis, the current recom-

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mendation calls for a combination of ampicillin and chloramphenicol as initial therapy. The isolated organism should be tested for betalactamase production and if this is absent, treatment may continue with ampicillin alone. Treatment of disease from ampicillin-resistant organisms should be continued with chloramphenicol. This approach of using combined initial therapy is probably also sensible for a lifethreatening infection such as epiglottitis. As with meningitis, once the sensitivity of the organism is known, single drug therapy can be continued. For other severe, but not immediately life-threatening H. injluenzae infections, ampicillin alone should be adequate therapy unless sensitivity tests reveal resistance.

REFERENCES 1. Albright, R., Dienes, L., and Sulkowitch, H.: Pyelonephritis with nephrocalcinosis caused by Haemophilus injluenzae and alleviated by sulfanilamide. New Eng. J. Med. 110:357-360, 1938. 2. Alsever, R., Stiver, H., Dinerman, N., et al.: Haemophilus injluenzae pericarditis and empyema with thyroiditis in an adult. J.A.M.A., 230:1426-1427, 1974. 3. Anderson, P., Johnston, R., and Smith, D.: Human serum activities against HemophiIus injluenzae, type b. J. Clin. Invest., 51 :31-38, 1972. 4. Chen, W., Richards, R., Carpenter, R., et al.: Haemophilus injluenzae as an agent of urinary tract infection. West Indian Med. J., 25:158--161,1976. 5. ~how, A., Bushkell, L., Yoshikawa, T., et al.: Haemophilus parainjluenzae epiglottitis with meningitis and bacteremia in an adult. Amer. J. Med. Sci., 267:365-368, 1974. 6. Chunn, C., Jones, S., McCutchan, J., et al.: Haemophilus parainjluenzae infective endocarditis. Medicine, 56:99--113, 1977. 7. Crossley, U., Bigos, T., and Joffe, C.: Hemophilus injluenzae pericarditis. Amer. Heart J., 85:246-251, 1973. 8. Douglas, R., and Devitt, L.: Pneumonia in New Guinea. 1. Bacteriological findings in 632 adults with particular reference to Haemophilus injluenzae. Med. J. Aust., 1 :42-49, 1973. . 9. Duke, M., and Donovan, T.: Hemophilus injluenzae pericarditis with cardiac tamponade. Amer. J. Cardiol., 31 :778-780, 1973. 10. Ellner, P., and Shahidi, A.: Postpartum bacteremia due to Haemophilus injluenzae. Obstet. Gynecl., 34:403-405, 1969. 11. Ernst, E., Berger, S., Barza, M., et al.: Activity of cefamandole and other cephalosporins against aerobic and anaerobic bacteria. Antimicrob. Agents Chemother., 9:852-855, 1976. 12. Everett, D., Rahn, A., Adaniya, R., et al.: Haemophilus injluenzae pneumonia in adults. J.A.M.A., 238:319-321, 1977. 13. Eykyn, S., Thomas, R., and Phillips, 1.: Haemophilus injluenzae meningitis in adults. Brit. Med. J., 2:463-465, 1974. 14. Farrand, R.: Haemophilus injluenzae infections of the genital tract. Med. Microbiol., 4:357-358, 1971. 15. Feigin, R., Richmond, D., HosIer, M., et al.: Reassessment of the role of bactericidal antibody in Hemophilus injluenzae infection. Amer. J. Med. Sci., 262:338--346, 1973. 16. Fothergill, L., and Wright, J.: Influenzal meningitis: The relationship of age incidence to the bactericidal power of blood against the causal organism. J. Immunol., 24:273284,1933. 17. Gorfinkel, H., Brown, R., and Kabins, S.: Acute infectious epiglottitis in adults. Ann. Intern. Med., 70:289--294, 1969. 18. Graber, C., Gershanin, J., Levtroff, A., et al.: Changing pattern of neonatal susceptibility to Hemophilus injluenzae. J. Pediat., 78:948--950, 1971. 19. Gump, D., Tarr, P., Phillips, A., et al.: Bactericidal antibodies to Hemophilus injluenzae. Proc. Soc. Exper. BioI. Med., 138:76-80, 1971. 20. Ingram, D., Anderson, P., and Smith, D.: Countercurrent immunoelectrophoresis in the diagnosis of systemic diseases caused by Haemophilus injluenzae type b. J. Pediat., 81 :1156-1159, 1972. 21 Johnstone, J., and Lawry, H.: Acute epiglottitis in adults due to infection with Haemophilus injluenzae, type b. Lancet, 2:134-136,1967.

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22. Jorgensen, J., Lee, J., and Alexander, G.: Rapid penicillinase paper strip test for detection of Beta-Iactamase-producing Haemophilus injluenae and Neisseria gonorrhaeae. Antimicrob. Agents Chemother., 11: 1087-1088, 1977. 23. Kammer, R., Preston, D., Turner, J., et al.: Rapid detection of ampicillin-resistant Haemophilus injluenzae and their susceptibility to 16 antibiotics. Antimicrob. Agents Chemother., 8:91-94, 1975. 24. Kaplan, N., and Braude, A.: Haemophilus injluenzae infections in adults. Observations on the immune disturbance. Arch. Intern. Med., 101 :515-523, 1958. 25. Keefer, C., and Rammelkamp, C.: Hemophilus injluenzae bacteremia: Report of two cases recovering following sulfathiazole an sulfapyridine. Ann. Intern. Med., 16:1121-1227, 1942. 26. Krauss, D., Aronson, M., Gump, D., et al.: Hemophilus injluenzae septic arthritis. A mimicker of gonococcal arthritis. Arthrit. Rheum., 17:267-271, 1974. 27. Levin D., Schwartz, M., Matthay, R, et al.: Bacteremic Hemophilus injluenzae pneumonia in adults. Amer. J. Med., 62:219-224, 1977. 28. Lynn, D., Kane, J., and Parker, R.: Haemophilus parainjluenzae and injluenzae endocarditis: A review of 40 cases. Medicine., 56: 115-128, 1977. 29. Makela, P., Peltula, H., Kaphty, H., et al.: Polysaccharide vaccines of Group A Neisseria meningitidis and Haemophilus injluenzae, type b: A field ·trial in Finland. J. Infect. Dis., 136:543-550, 1977. 30. Michaels, R.: Increase in influenzal meningitis. New Eng. J. Med., 285:666-667, 1971. 31. Nixon, D., and Aisenberg, A.: Fatal Hemophilus injluenzae sepsis in an asymptomatic splenectomized Hodgkin's disease patient. Ann. Intern. Med., 77:69-71, 1972. 32. Norden, C.: Prevalence of bactericidal antibodies to Haemophilus injluenzae, type b. J. Infect. Dis., 130:489-494, 1974. 33. Norden, D., Callerame, M., and Baum, J.: Haemophilus injluenzae meningitis in an adult: Antibodies and Immunoglobulins. New Eng. J. Med., 282:190-194,1970. 34. Parke, J., Schneerson, R, Robbins, J., et al.: Interim report of a controlled field trial of immunization and capsular polysaccharides of Haemophilus injluenzae, type band Group C Neisseria meningitidis. J. Infect. Dis., 136:551-556, 1977. 35. Pittman, M.: Variation and type specificity in the bacterial species Haemophilus injluenzae. J. Exper. Med., 53:471-495, 1931. 36. Quintliani, R, and Hymans, P.: The association of bacteremic Haemophilus injluenzae pneumonia in adults with typable strains. Am. J. Med., 50:781-786, 1971. 37. Raff, M., and Dannaher, C.: Hemophilus injluenzae septic arthritis in adults. J. Bone Joint Surg., 56A:408-412, 1974. 38. Robbins, J., Schneerson, R., Argaman, M., et al.: Haemophilus injluenzae type b: Disease and immunity in humans. Ann. Intern. Med., 78:259-269,1973. 39. Schiffer, M., Schneerson, R., Machawry, J., et al.: Clinical, bacteriological, and immunological characterisation of ampicillin-resistant Haemophilus injluenzae type b. Lancet, 2:257-259, 1974. 40. Sigwert, V., and Raslavicius, P.: Cholecystitis associated with Hemophilus injluenzae. Southern Med. J., 65:503-504, 1972. 41. Smith, C., Kanner, R, Golden, C., et al.: Haemophilus injluenzae and Haemophilus parainjluenzae in chronic obstructive pulmonary disease. Lancet. 1 :1253-1255, 1976. 42. Thornsberry, C., and Kirven, L.: Ampicillin resistance in Haemophilus injluenzae as determined by a rapid test for beta-Iactamase production. Antimicrob. Agents Chemother., 6:653-654, 1974. 43. Turk, D., and May, J.: Haemophilus injluenzae. London, English Universities Press, 1967. 44. Weitzman, S., Aisenberg, A., Siber, G., et al.: Impaired humoral immunity in treated Hodgkin's disease. New Eng. J. Med., 297:245-248, 1977. 45. Whisnant, J., Roegentine, G., Gralnick, M., et al.: Host factors and antibody response in Haemophilus injluenzae type b meningitis and epiglottitis. J. Infect. Dis., 133:448-455, 1976. Montefiore Hospital 3459 Fifth Avenue Pittsburgh, Pennsylvania 15213

Hemophilus influenzae infections in adults.

Symposium on Infectious Diseases Hemophilus Influenzae Infections in Adults Carl W. Norden, M.D. * Hemophilus injluenzae, a gram-negative pleomorphi...
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