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Surveillance Programme UK 1971-5. In: Viral diseases of the fetus andnewborn. Philadelphia: Saunders, 1978: 17-96.

10. Public Health Laboratory Service. TORCH screening reassessed.London: PHLS, 1990.

11. Public Health Laboratory Service Working Party on Fifth Disease.Prospective study of human parvovirus (B19) infection in pregnancy.Br Med J 1990; 300: 1166-70.

12. Aycock WL. The frequency of poliomyelitis in pregnancy. N Engl J Med1941; 225: 405-08.

13. Kleinman H, Prince JT, Mathey WE, Rosenfield AB, Bearman JE,Syverton JT. Echo 9 virus infection and congenital abnormalities: anegative report. Pediatrics 1962; 29: 261-69.

14. Modlin JF. Fatal echovirus II disease in premature neonates. Pediatrics1980; 66: 775-79.

15. Laforet EG, Lynch CL. Multiple congenital defects following maternalvaricella. N Engl J Med 1947; 236: 534-37.

16. Buchdahl R, Hird M, Gamsu H, Tapp A, Gibb D, Tzannatos C.Listeriosis revisited: the role of the obstetrician. Br J Obstet Gynaecol1990; 97: 186-89.

17. Spencer JAD. Perinatal listeriosis. Br Med J 1987; 295: 349.18. Matthews TG, Warshaw JB. Relevance of gestational age distribution of

meconium passage in utero. Pediatrics 1979; 64: 30-31.19. Pass RF, Stagno S, Myers GJ, Alford CA. Outcome of symptomatical

congenital cytomegalovirus infection: results of long term longitudinalfollow-up. Pediatrics 1980; 66: 758-62.

20. Saigal S, Lung KO, Larke RPB, Chemesky MA. The outcome inchildren with congenital cytomegalovirus infection. Am J Dis Child1982; 136: 896-901.

21. Kuman ML, Nankerns GA, Jacobs IB. Congenital and postnatallyacquired cytomegalovirus infections: long term follow-up. J Pediatr1984; 104: 674-79.

22. Griffiths PD. Cytomegalovirus. In: Zuckerman AJ, Banatvala JE,Pattison JR, eds. Principles and practice of clinical virology.Chichester: Wiley, 1987: 75-109.

23. Preece PM, Pearl KN, Peckham CS. Congenital cytomegalovirusinfection. Arch Dis Child 1984; 59: 1120-26.

24. Best JM. Congenital cytomegalovirus infection. Br Med J 1987; 294:1440-41.

25. PHLS Working Party on Laboratory Diagnosis of Rubella: summary ofrecommendations of the PHLS working party. PHLS Microbiol Dig1988; 5: 49-52.

26. Katz SL, Wilfert CM. Human immunodeficiency virus infection ofnewborns. N Engl J Med 1989; 320: 1687-88.

27. Balfour AH, Fleck DG, Hughes HPA, Sharp D. Comparative study ofthree tests (dye test; indirect haemagglutination test, latex agglutinationtest) for the detection of antibodies to Toxoplasma gondii in human sera.J Clin Pathol 1982; 35: 228-32.

Smoking and immunityThe immunological effects of cigarette smoking havebeen studied extensively, the impetus for these

investigations being the belief that alterations inimmune function might explain some of the

inflammatory and neoplastic complications of

smoking. Nevertheless, it is very difficult to

distinguish pathogenetically important alterations inimmunological status from irrelevant epiphenomena.For example, how much importance should oneattach to the changes in lymphocyte subpopulationsinduced by cigarette smoking? These alterations arenot well correlated with any in-vivo or in-vitrofunctional changes and still less can they be directlyrelated to disease. Lymphocyte subpopulationanalysis is affected by many other stimuli-eg, stress,infection, time of sampling, and drug ingestion-sointerpretation in relation to a single factor such assmoking status is difficult if not impossible. Theimportance of quality as well as quantity of an immuneresponse must not be overlooked.

In the assessment of functional changes it is

important to realise that the immune system is both

complex and compartmentalised. There is extensivetraffic of cells between the main compartments, eachwith its own discrete structural organisation in whichcells and short-range mediators can move. Thusstudies of functional properties of cells may givevariable results depending on the source of the cells,and such results can be applied only to the

compartment from which the cells were drawn.Functional studies on lymphocytes are usually doneon peripheral blood, for convenience, but these cellsmerely represent cells in transit; effector cells ofinterest may have emigrated from the bloodstream to adifferent compartment such as the mucosal lymphoidtissue. Lin and colleagues2 have illustrated this pointvery effectively in a study of alveolar and bloodmonocytes in smokers. These observations may helpto explain the diverse results of functional assays oflymphocytes from smokers discussed by Holt.1

Smoking is especially difficult to study because of thecomplexity of the smoke and the variation in its effectsat different levels of the respiratory tract as a result ofselective absorption and deposition. It is also

necessary to consider the effects produced at themucosal surface by poorly or non-absorbed

components by comparison with effects of systemicabsorption of constituents, which may influencedistant immunological compartments and possiblylymphocyte maturation and traffic. Moreover, it is notclear how immunological variables are altered inrelation to ingestion of certain compounds or to theabsolute quantity ingested since most studies have notattempted to correlate changes with chemicalmeasures of cigarette ingestion.One compartment of special interest is the mucosal

immune system. Barton and colleagues3 latelyreported the concentrations of salivary IgA from theparotid gland in smokers and patients with epithelialtumours of the head and neck. They showed areduction in salivary IgA and an increase in IgMconcentration in smokers that were independent offlow rate. Whilst this result broadly accords with moststudies on mixed saliva, there are some discrepancies,which Barton et al address. By contrast, Warr et al’reported that IgA concentrations in bronchoalveolarlavage fluid are normal in smokers compared with anon-smoking control group whereas IgG levels areincreased.4 This discrepancy may reflect the fact thatthe lower respiratory tract lymphoid tissue is closer tothe mucosal surface and so is more exposed to

components of cigarette smoke than is lymphoidtissue in the parotid gland. The results obtained withlavage fluid have not been directly compared withthose of saliva; such studies would directly address thequestion of smoking-related changes in immunestatus at different levels in the respiratory tract.The functional role of secreted IgA is probably to

deal with mucosal pathogens and foreign antigens.IgA deficiency is the commonest primaryimmunodeficiency, affecting between 1 in 400 and 1 in

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600 people. It has not been unequivocally and causallyassociated with disease except in patients withconcomitant IgG subclass deficiency or T-cell

dysfunction, although there is a strong associationwith autoimmune conditions, perhaps related to afailure to prevent the passage of antigens from lumento mucosa. Thus a smoking-related reduction but notcomplete absence of secreted IgA may not be

important per se. Raised secreted IgG or IgMconcentrations may be a natural compensatorymechanism. Nonetheless, this area remainscontroversial and some immunologists maintain thatIgA deficiency is always important in the generation ofill-health.5 Since the picture is still unclear in primaryIgA deficiency, it is impossible to interpret thefunctional relevance of the smoking-related changes inmucosal immunoglobulin secretion.

In the context of respiratory mucosal immunity,there is also evidence that smoking is related to

changes in specific IgE and precipitating IgG.Cigarette smoking appears to raise total serum IgE;6,7the nature of this increase, which does not correlatewith rises in specific IgE to common aeroallergens,and its relation to increased bronchial hyperreactivityare unclear, although several hypotheses have beenadvanced.8 Under certain conditions smoking seemsto predispose to IgE-mediated asthma--eg, in asthmainduced by tetrachlorophthalic anhydride.9 Patientswith extrinsic allergic alveolitis who smoke havereduced levels of IgG precipitating antibodies to

fungal and avian antigens, 10-12 although it is not clearthat smoking is protective. Anderson and colleaguesl2are one of the few groups to have made a serious

attempt to relate the immunological changes that theyfind to an objective measure of smoking, in this caseend-tidal carbon monoxide.

These alterations of mucosal immunoglobulinproduction are important, not so much in their ownright but as a marker of underlying alterations inimmune function. Production of immunoglobulin isthe final common pathway of a complex series ofinteractions that start with the uptake and processingof antigen by specialised antigen-presenting cells. Inthe mucosa, this function is carried out byLangerhans’ cells, so it is interesting that cervicalmucosal Langerhans’ cells are reduced in smokers.13It is unclear how smoking mediates this effect,although Muller et a114 have shown that a chemicalcarcinogen induces depletion of these cells in

laboratory animals. It is also not clear whether thiseffect is specific to cervical epithelium. Inbronchoalveolar lavage fluid, there is evidence that thereverse situation might apply, with an increase ofLangerhans’ cells in the fluid from smokers comparedwith controls.1s This observation has been used to

explain the strong positive association of histiocytosisX with cigarette smoking, since the granulomas in thiscondition are thought mainly to involve Langerhans’cells.16 Although it is attractive to suggest that the

increased frequency of cervical neoplasia in smokersmay be related to the reduction in Langerhans’ cells,this is by no means proven; Morris et al 17 have shownin cervical mucosa that wart virus infection reducescell numbers, possibly by a direct effect of the virus,whereas intraepithelial neoplasia increases cell

numbers, presumably associated with an activeimmune response to the malignant cells. Thus thesmoking-related reduction of Langerhans’ cells mightpredispose to viral infection and a subsequent poorresponse to neoplastic change. However, changes innumbers alone do not guarantee abnormal functionbecause the cells could be performing normally bytaking up antigen and travelling to the regional lymphnodes. The reduction might be because antigen is

stimulating emigration in excess of recruitment. In thesame way that IgA is the end-product of the immunecascade, antigen uptake and presentation is merely theinitiating step, and in between these two lie manyother cells and mediators that must be systematicallyinvestigated before we can attribute a certain

smoking-related side-effect to alterations of a

particular cell type.The relation between smoking and integrated

immune function remains obscure, especially ourunderstanding of how or even whether the alterationsin immune function play an important part in themajor smoking-related diseases. One of the maindifficulties in studying the immunology of smoking orof other diseases is how to move from the stage of

quantification of cells or products and relate thesechanges to functional alterations in immunologicalcompartments and then link these alterations directlyto specific diseases. Perhaps a more holistic approachto immune function is required.

1. Holt PG. Immune and inflammatory function in cigarette smokers.Thorax 1987; 42: 241-49.

2. Lin C-C, Huang W-C, Lin C-C. Chemiluminescence and antibody-dependent, cell-mediated cytotoxicity between human alveolar

macrophages and peripheral blood monocytes in smokers, non-smokers and lung cancer patients. Chest 1989; 95: 553-57.

3. Barton JR, Riad MA, Gaze MN, Maran AGD, Ferguson A. Mucosalimmunodeficiency in smokers and in patients with epithelial head andneck tumours. Gut 1990; 31: 378-82.

4. Warr GA, Martin RR, Sharp PM, Rossen RD. Normal human bronchialimmunoglobulins and proteins: effects of cigarette smoking. Am RevRespir Dis 1977; 116: 25-30.

5. Buckley RH. Humoral immunodeficiency. Clin Immunol Immunopathol1986; 40: 13-24.

6. Burrows B, Halonen M, Barbee RA, Lebowitz MD. The relationship ofserum immunoglobulin E to cigarette smoking. Am Rev Respir Dis1981; 124: 523-25.

7. Gerrard JW, Heiner DC, Ko CG, Mink J, Meyers A, Dosman JA.Immunoglobulin levels in smokers and nonsmokers. Ann Allergy 1980;44: 261-62.

8. Pride N. Smoking, allergy and airways obstruction: revival of the ’Dutchhypothesis’. Clin Allergy 1986; 16: 3-6.

9. Howe W, Venables KM, Topping MD, et al. Tetrachlorophthalicanhydride asthma: evidence for specific IgE antibody. J Allergy ClinImmunol 1983; 71: 5-11.

10. Morgan DC, Smyth JT, Lister RW, Pethybridge RJ. Chest symptomsand farmer’s lung a community survey. Br J Indust Med 1973; 30:259-65.

11. McSharry C, Banham SW, Lynch PP, Boyd G. Antibody measurementin extrinsic allergic alveolitis. Eur J Respir Dis 1984; 65: 259-65.

12. Anderson K, Morrison SM, Bourke S, Boyd G. Effect of cigarette

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smoking on the specific antibody response in pigeon fanciers. Thorax1988; 43: 798-800.

13. Barton SE, Maddox PH, Jenkins D, Edwards R, Cuzick J, Singer A.Effect of cigarette smoking on cervical epithelial immunity: a

mechanism for neoplastic change? Lancet 1988; ii: 652-54.14. Muller HK, Halliday GM, Knight BA. Carcinogen-induced depletion of

cutaneous Langerhans’ cells. Br J Cancer 1985; 52: 81-85.15. Casolaro MA, Bemaudin J-F, Saltini C, Ferrans VJ, Crystal RG.

Accumulation of Langerhans’ cells on the epithelial surface of the lowerrespiratory tract in normal subjects in association with cigarettesmoking. Am Rev Respir Dis 1988; 137: 406-11.

16. Chollet S, Soler P, Dournovo P, Richard MS, Ferrans VJ, Basset F.Diagnosis of pulmonary histiocytosis X by immunodetection ofLangerhans’ cells in the bronchoalveolar lavage fluid. Am J Pathol1984; 115: 225-32.

17. Morris HHB, Gatter KC, Sykes G, Casemore V, Mason DY.Langerhans’ cells in human cervical epithelium: effects of wart virusinfection and intraepithelial neoplasia. Br J Obstet Gynaecol 1983; 90:412-20.

KIKUCHI’S DISEASE

The histological appearances in the lymph nodes of patientswith Kikuchi’s disease (histiocytic necrotising lympha-denitis) are readily recognised, but a recent flurry ofcase-reportsl-6 suggests that, outside Japan (where thecondition was first described in 1972), the clinicalmanifestations are not widely appreciated. The diseaseusually affects young women-the female to male ratio ismore than four to one-and has been recorded from manycountries. However, the predominance of reports fromJapan and the fact that many of the patients in Europe andthe USA have been of Asian descent may point to a racial orgenetic susceptibility. Typically, patients present with apainless but sometimes tender unilateral cervical

lymphadenopathy. Occasionally the adenopathy occurs atother sites-isolated involvement of mediastinals or

retroperitoneal8 lymph nodes has been described-and inup to 20% of cases it may be generalised. Splenomegaly isLmcor=on.11,9 Fever is present in about a third of cases andsometimes there is neutropenia or lymphocytosis.9Abnormal liver function has lately been described as thepresenting features and arthralgia, rashes, and

epididymitis have also been recorded.9,lO The disease usuallyresolves spontaneously within three months although it canpersist for a year or so and may even recur. 6,8

Within affected lymph nodes the T-cell regions arealmost exclusively involved: there is patchy paracorticalnecrosis consisting of eosinophilic fibrinoid material thatcontains large quantities of karyorrhectic nuclear debris(nuclear dust). The necrosis is surrounded by a

polymorphous cell population of foamy histiocytes,macrophages (some phagocytosing nuclear debris), andreactive T cells.9 Plasma cells are rare and there is a

characteristic absence of polymorphonuclear leucocytes. Itis still unclear whether the abnormal T cells are cytotoxic/suppressor or helper/inducer cells, and the proportions ofeach type may change with the stage of the illness. Theproliferation of reactive histiocytes and effacement ofnormal lymph node architecture may be erroneouslydiagnosed as malignant lymphoma or Hodgkin’s disease, z10but most other causes of fever and lymphadenopathy arereadily distinguished by the histological appearance.The aetiology of Kikuchi’s disease is unclear. Kikuchi

himself thought it was a form of toxoplasmosis," andoccasional cases have been associated with Yersiniaenterocolitica infection.5,12 A possible role for human

herpesvirus 6 has also been suggestedY Nevertheless, inmost cases there is no evidence of recent infection with any

of these organisms. One interpretation is that Kikuchi’sdisease is a self-limited systemic-lupus-erythematosus(SLE)-like autoimmune condition induced by infectedlymphocytes.14 Some support for this concept comes fromthe report of patients with Kikuchi’s lymphadenitis,diagnosed by experienced histopathologists, who

subsequently manifested frank SLE,9 but such progressionmay be coincidental. Malignant transformation does notseem to occur and only one fatality (from myocardialdamage) has been reported during the acute phase z

1. Bowness P, Dutoit SH. Kikuchi’s disease as a cause of fever and cervicallymphadenopathy. J Infect 1988; 16: 310-11.

2. Chan JKC, Wong K-C, Ng C-S. A fatal case of multicentric Kikuchi’shistiocytic necrotizing lymphadenitis. Cancer 1989; 63: 1856-62.

3. Bailey EM, Klein NC, Cunha BA. Kikuchi’s disease with liver

dysfunction presenting as fever of unknown origin. Lancet 1989; ii: 986.4. Kapadia V, Robinson BA, Angus HB. Kikuchi’s disease presenting as

fever of unknown origin. Lancet 1989; ii: 1519.5. Pearl D, Strauchen JA. Kikuchi’s disease as a cause of fever of unknown

origin. N Engl J Med 1989; 320: 1147-48.6. Nieman RB. Diagnosis of Kikuchi’s disease. Lancet 1990; 335: 295.7. KikuchiM. Lymphadenitis showing focal reticulum cell hyperplasia with

nuclear debris and phagocytes: a clinicopathological study. NipponKetsueki Gakkai Zasshi 1972; 35: 379-80 (in Japanese).

8. Rudniki C, Kessler E, Zarfati M, Turani H, Bar-Ziv Y, Zahavi I.Kikuchi’s necrotizing lymphadenitis: a cause of fever of unknownorigin and splenomegaly. Acta Haematol (Basel) 1988; 79: 99-102.

9. Dorfman RF, Berry GJ. Kikuchi’s histiocytic necrotizing lymphadenitis:an analysis of 108 cases with emphasis on differential diagnosis. SeminDiagn Pathol 1988; 5: 329-45.

10. Turner RR, Martin J, Dorfman RF. Necrotizing lymphadenitis: a studyof 30 cases. Am J Surg Pathol 1983; 7: 115-23.

11. Kikuchi M, Yoshizumi T, Nakamura H. Necrotizing lymphadenitis:possible acute toxoplasmic infection. Virch Arch [A ] 1977; 376:247-53.

12. Feller AC, Lennert K, Stein H, Bruhn H-D, Wuthe H-H.

Immunohistology and etiology of histiocytic necrotizinglymphadenitis: report of three instructive cases. Histopathology 1983; 7:825-39.

13. Eizuru Y, Minematsu T, Minamishima Y, et al. Human herpesvirus 6 inlymph nodes. Lancet 1989; i: 40.

14. Imumura M, Ueno H, Matsumura A, et al. An ultrastructural study ofsubacute necrotizing lymphadenitis. Am J Pathol 1982; 107: 292-99.

PATIENT CARERS

The wives of men who have heart attacks merit attentionboth as carers and as patients in their own right. In a study inOntario,l most such wives consulted their doctor about theirown health in the three months after the husband’s infarc-tion. We do not know what they consulted about or whetherthese women could be differentiated from those who did notconsult a doctor by the Quality of Life Questionnaire forCardiac Spouses, but there is no doubt that their suffering isreflected in the consultation rates, and that the disabilityassociated with this suffering impaired their effectiveness asthe main carers for these cardiac patients. The Canadianwork confirms an earlier study in Oxford, in which thepsychological reaction of the wives was found to be evengreater than that of the patients themselves.2What can be done to help "cardiac spouses" cope with

their own crisis and at the same time enable them to mitigatethe frightening disability and anxiety experienced by theirhusbands? Information leaflets, personal counselling, andself-help groups are among the resources available to thesewomen, who are presented with the problem of havinghusbands at home before time, possibly behaving like bearswith sore heads and without the sanction of normalretirement processes, gold watches, or inscribed silversalvers. Some may even feel guilty about the thought which