SEVERE PNEUMONIA—A CONTINUING STORY

1064 SEVERE PNEUMONIA—A CONTINUING STORY

discovery and isolation of Legionella pneumophila by inoculation of necropsy material into guineapigs and thence into the yolk-sacs of embryonated hens’ eggs’ has led to investigations of other agents which refused to grow on ordinary culture media. Microbiological squirrels have raided their deep-freezers for longstored guineapig and egg tissues in the hope that something might grow on the media developed for legionellas. As far as L. pneumophila is concerned, these studies have revealed that the first strain (OLDA) was isolated from the blood of a febrile patient2,3 in 1947 and that Pontiac fever occurring in 1968 was due to L. pneumophila of serogroup 1.4,5 Three "rickettsia-like" organisms isolated in 1943 ("TATLOCK") and 1959 (WIGA and HEBA) by guineapig inoculation have also been shown to grow on media suitable for the growth of L. pneumophila.3,6 The TATLOCK organism was isolated in 1943 from the blood of a serviceman at Fort Bragg, North Carolina, with an unusual febrile illness known as Fort Bragg fever (or "pretibial" fever because patients had a rash over the tibia). Although there was no proof that the organism was responsible for the illness, Tatlock published his findings in the hope that the role of the organism might eventually be clarified. The occurrence of a rash in his case is interesting since the organism designated as HEBA was isolated from the blood of a patient with . suspected pityriasis rosea.8 The WIGA organism (also designated as atypical legionella-like organism—ALLO19) was isolated from the lung of a scuba-diver who died of pneumonia. A related organism ALL02 was isolated in 1978 from the lungs of a man with untreated lymphatic leukasmia who got pneumonia after immersion in swampy water after a boating acciTHE

dent9. The most recently described gram-negative rod to be isolated by guineapig inoculation and then transferred to the yolk sac but not, at first, on to artificial culture media, is the Pittsburgh pneumonia agent originally isolated from two renal transplant patientslO and subsequently identified in a further six immunosuppressed patients -reviewed in Pittsburgh" and five patients 1. McDade

JE, Shepard CC, Fraser DW, Tsai TR, Redus MA, Dowdle WR. Legionnaires’ disease. Isolation of a bacterium and demonstration of its role in other respiratory disease. N Engl J Med 1977; 297: 1197-1203. 2. Jackson EB, Crocker TT, Swadel JE. Studies on two rickettsia-like agents probably isolated from guineapigs. Bacterial Proc 1952, p. 119. 3. McDade JE, Brenner DJ, Bozeman FM. Legionnaires’ disease bacterium isolated in 1974. Ann Intern Med 1979; 90: 659-61. 4. Glick TH, Gregg MB, Berman B, Wallison G, Rhodes WW Jr, Kassanoff I. Pontiac fever. An epidemic of unknown aetiology in a Health Department. I. Clinical and epidemiologic aspects. Am J Epidemiol 1978; 107: 149-60. 5. McKinney RM, Thacker R, Harris PP, Lewallen KR, Hébert A, Edelstein PH, Thomason BM. Four serogroups of Legionnaires’ Disease bacteria defined by direct immunofluorescence. Ann Intern Med 1978; 90: 621-24. 6. Hébert GA, Moss CW, McDougal LK, Bozeman FM, McKinney RM, Brenner DJ. The rickettsia-like organisms TATLOCK (1943) and HEBA (1959): bacteria phenotypically similar to, but genetically distinct from Legionella pneumophila and the WIGA bacterium. Ann Intern Med 1980;

92: 45-52. 7. Tatlock H. A rickettsia-like

organism recovered from guineapigs. Proc Soc Exp Biol Med 1944; 57: 95-99.. 8. Bozeman FM, Humphries JW, Campbell JM. A new group of rickettsia-like agents recovered from guineapigs. Acta Virol (Praha) 1968; 12: 87-93. 9. Cordes LG, Gorman GW, Wilkinson HW, Fikes BJ, Fraser DW. Atypical legionella-like organisms: fastidious water-associated bacteria pathogenic

for man. Lancet 1979; ii: 927-30. 10. Pascule AW, Myerowitz RL, Rinaldo CR Jr. New bacterial agent of pneumonia isolated from renal transplant recipients. Lancet 1979; ii: 58-61. 11. Myerowitz RL, Pascule AW, Dowling JN, Pazin GJ, Puerzer M, Yee RB, Rinaldo CR Jr, Hakala TR. Opportunistic lung infection due to "Pittsburgh pneumonia agent". N Engl J Med 1979; 301: 953-58.

receiving high-dose steroid therapy in Charlottesville.12 This organism has now been shown to grow, as do the other bacilli mentioned and L. pneumophila, on charcoal-yeast-extract agar and to be fastidious gram-negative bacilli apparently identical to the organism isolated by Tatlock in 1943.13 Studies on the relations of all these bacteria to each other and also to a similar organism (TEX-KL) isolated from a fatal pneumonia in a 60-year-old, immunosuppressed man 14 have revealed that TATLOCK, HEBA, and the Pittsburgh pneumonia agent are identical. WIGA, TATLOCK, and TEX-KL have a similar fatty acid profile on gas-liquid chromatography distinct from L. pneumophila. Nevertheless, they are distinct from each other both serologically in terms of somatic (but not flagellar) antigens, and genetically as determined by DNA homology studies. So, in the present state of the art (an important qualification), there are six serogroups of L. pneumophila, all of which have now been isolated from patients (often debilitated or immunosuppressed) with pneumonia as well as from water or water-contaminated sources (e.g., the air-conditioning system in the Public Health Service building in Pontiac), three serogroups of similar flagellated gram-negative rods also isolated from patients with pneumonia, and also a similar organism (ALL03)9 as yet isolated only from water. In addition to pneumonia, L. pneumophila has been associated with transitory mild respiratory upset (Pontiac fever) and the TATLOCK group with a mild febrile illness, both in previously healthy subjects. Hence, although all these bacteria may be associated with severe illness, the possibility of milder illness exists. The deep freezers have yielded not only a rich harvest of bacteria, but also sera showing antibodies to these agents. Retrospective serology by the fluorescent antibody technique has incriminated legionellas in the 1965 pneumonia outbreaks in St Elizabeth’s Hospital, Washington,I5 in the diseases afflicting travellers returning from Spain to Scotland in 197316 and in the troubles of those attending an Oddfellows congress in the same hotel in Philadelphia as that associated with the 1976 outbreak of legionnaires’ disease,17 as well as confirming the prescence of legionella antibodies in cases of Pontiac fever.4,18 The disease spectrum of both legionella and the associated bacteria is puzzling. The mild disease at Pontiac4 contrasts with the severe pneumonia normally associated with legionella infection, as does the Fort Bragg Rogers BH, Domowitz GR, Walker GK, Harding SA, Sande M. Opportunistic pneumonia. A clinicopathological study of five cases, caused by an unidentified acid-fast bacterium. N Engl J Med 1979; 301 :959-61. 13. Hébert GA, Thomason BM, Harris PP, Hicklin MD, McKinney RM. "Pittsburgh pneumonia agent", a bacterium phenotypically similar to Legionella pneumophila and identical to the TATLOCK bacterium. Ann

12.

Intern Med 1980; 92: 53-54. 14. Lewallen KR, McKinney RM, Brenner DJ, Moss W, Dail DH, Thomason BM, Bright RA. Newly identified bacterium phenotypically resembling, but genetically distinct from, Legionella pneumophila an isolate in a case of pneumonia. Ann Intern Med 1979; 91: 831-34. 15. Thacker SB, Bennett JV, Tsai TF, Fraser DW, McDade JE, Shepard CC, Williams KH Jr, Stuart WH, Dull HB, Eickhoff TC. An outbreak in 1965 of severe respiratory illness caused by the Legionnaires’ disease bacterium.

J Infect Dis 1978; 138: 512-19. 16. Reid D, Grist NR, Nájera R. Illness associated with "package tours": a combined Spanish-Scottish study. Bull World Health Org 1978; 56: 117-22. 17. Terranova W, Cohen ML, Fraser DW. 1974 outbreak of Legionnaires’ disease diagnosed in 1977. Clinical and epidemiological features. Lancet 1978; ii: 122-24. 18. Eickhoff TC. Epidemiology of Legionnaires’ disease. Ann Intern Med 1979; 90: 499-502.

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fever with the severe pneumonia seen in many of those infected with bacteria of the WIGA, TATLOCK, and TEX-KL groups. There is much to be learned about these infections and some of the answers may still be in someone’s deep-freezer. VIRUSES AND FEBRILE CONVULSIONS

ALTHOUGH no explicit link between fever and convulsions has been discovered,’2 epidemiological studies suggest an association with upper-respiratory-tract infections and other presumed viral illnesses.34(Other factors may include age, genetic predisposition, and the degree of pyrexia.) Lewis et aJ.5 report that 63 (89%) of 73 children admitted to hospital after a first febrile convulsion had evidence of viral infection. Viruses were isolated from 46 children, aged between six months and five years; in the others the only evidence of infection was serological (2) or the presence of interferon in serum (15). The viruses detected included 22 adenoviruses, 17 enteroviruses, and 9 other commonly occurring viruses. In 20 patients (27%) there was evidence of systemic spread, indicated by isolation of viruses from urine (13 cases), blood (12 cases), or cerebrospinal fluid (CSF) (4 cases). In addition, potential bacterial pathogens were isolated from 21 cases (29%), 3 of these from systemic sites. The mean duration of illness before convulsions was 13.4 h, and the initial clinical features included upperrespiratory-tract infection, rash, and gastrointestinal upset. In 49 patients convulsions were designated "simple" and in 24 "complex"-that is, the fit lasted more than 15 min, or there was more than one, or there were central-nervous-system localising signs. No differences between simple and complex cases were evident on microbiological, hxmatological, or CSF analysis. 4 children had been immunised within two weeks of the convulsion. In 2 who had received triple vaccine, coincidental viral infections were regarded as more likely factors than immunisation, while 1 had received measles vaccine 10 days, and 1 cholera vaccine 1½h, previously. Lewis and co-workers conclude that common viruses can invade the blood, CSF, and presumably the central nervous system (CNS), and suggest that transient viraemia probably occurred in all their cases to produce fever and convulsions by affecting the susceptible immature brain. Whether the convulsions observed were classical epileptiform paroxysms or related to vagal reflexes6 was not

investigated. Young children

are susceptible to many epidemic and endemic viruses. These give rise to a wide variety of clinical diseases, but symptomless infection and pro-

1 Lennox WG. Significance of febrile convulsions. Pediatrics 1953; 11: 341-57. 2. Ounsted C. Bridges joining the basic sciences and clinical practice. In: Brazier MA, Coccani F, eds. Brain dysfunction in infantile febrile convulsions. New York: River Press, 1976: 241-46. 3 Miller FJW, Court SDM, Walton WS, Knox EJ. Growing up in Newcastle upon Tyne. A continuing study of health and illness in young children within their families. London: Oxford University Press, 1960: 369. 4 Lennox-Buchtal MA. Febrile convulsions—a reappraisal. Electroenceph

Clin Neurophysiol 1973; suppl 32, 47-55. 5. Lewis HM, Parry JV, Parry RP, Davies HA, Sanderson PJ, Tyrrell DAJ, Valman HB. Role of viruses in febrile convulsions. Arch Dis Child 1979; 54: 869-76. 6 Stephenson JBP. Two types of febrile seizure: Anoxic (syncopal) and epileptic mechanisms differentiated by oculocardiac reflex. Br Med J 1978; ii: 726-28.

longed excretion of virus are also well recognised,7-9 hampering interpretation of an association between viral infection and disease. Symptomless infection and prolonged carriage of virus are seen particularly with adenoviruses and enteroviruses. An antibody rise coinciding with isolation of virus, or isolation of virus from the site of the pathological process, is more convincing evidence of an s’tiological role, but Lewis did not find such evidence in all cases with febrile convulsions. With the introduction of new techniques, such as electron microscopy for study of infant diarrhœa,10 the number of children identified with viral infections can be increased but the atiological role for additional agents is still not clear. Likewise with febrile convulsions, interferon studies increased the number of children with detectable viral infections to 89%, but do not clarify their role if any in producing febrile convulsions. By routine techniques viral infections are found in children with febrile convulsions about as often as in children admitted to hospital with respiratory infection." This suggests that, if newer techniques were applied to both groups, neither group would have more infections than the other. If viruses cause febrile convulsions what is the mechanism? Because of the large number of different viruses detected the convulsions cannot be attributed to any single agent. Lewis et al. detected invasion of the CNS in 3 cases of adenovirus and 1 of parainfluenza infection. This indicates the ability of these viruses to reach the CNS but does not indicate neuropathogenicity per se. The role of adenoviruses in CNS disease is not clear, but they have been isolated from neural tissue of children who died without obvious associated neurological disease.12 Comparative CSF studies on live children without neurological signs are not possible. Enteroviruses are common causes of aseptic meningitis and can be isolated from CSF,13 but they can also be isolated from CSF in the absence of convulsions or gross CNS disease. On the other hand, in proven herpes simplex encephalitis, virus is rarely isolated from lumbar CSF although present in brain tissue. Poliovirus is likewise rarely detectable in the CSF in cases of paralytic poliomyelitis. Our scanty knowledge of the role of some viruses in CNS disease and of the frequency with which viruses enter the CNS without causing disease makes interpretation difficult. Virsemia may be the key to virus-induced convulsions, but virsemia is a common feature of many viral infections, particularly with enteroviruses and measles, while it has been reported in adenovirus, 12,14 rhinovirus,12 and

7. Fox JP, Brandt CD, Wasserman FE, Hall CE, Spigland I, Kogon A, Elveback LR. The Virus Watch Program: a continuing surveillance of viral infections in metropolitan New York families. VI. Am J Epidemiol 1969; 89: 25-50. 8. Patterson WJ, Bell EJ. Poliomyelitis in a nursery school in Glasgow. Br Med J 1963; i: 1574-76. 9. Stott EJ, Bell EJ, Eadie MB, Ross CAC, Grist NR. A comparative virological study of children in hospital with respiratory and diarrhoeal illnesses. J

Hyg 1967, 65: 9-23. 10. Madeley CR. Viruses in stools. J Clin Path 1979; 32: 1-10. 11. Hilleman MR, Hamparian VV, Ketler A, Reilly CM, McClelland L, Cornfield D, Stokes J. Acute respiratory illness among children and adults.

JAMA 1962; 180: 445-53. Urquhart GED, Grist NR. Virological studies of sudden, unexplained infant deaths in Glasgow 1967-70. J Clin Path 1972; 25: 443-46. 13. Grist NR, Bell EJ, Assaad F. Enteroviruses in human disease. Progr Med 12.

Virol 1978; 24: 114- 57. 14. Hartwell WV, Love GJ, Eidenbock MP. Adenovirus of infectious hepatitis. Science 1966, 152: 1390.

in

blood clots from

cases