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TOXOPLASMOSIS DIAGNOSIS ANDIMMUNODEFICIENCY

INFECTION by Toxoplasma gondii is common throughoutthe world, and by adult life 20-40% of individuals in the UKand USA have antibody to this protozoan. 1,2 Nearly all theinfections are subclinical and pass unnoticed, so that the needfor diagnosis seldom arises. Until lately the four clinicalconditions that stimulated clinicians into diagnostic activitywere: congenital infection, when the baby is either born withone or more of Sabin’s tetrad (microcephaly, internal hydro-cephalus, choroidoretinitis, intracerebral calcification) or

subsequently shows evidence of intracranial or ocular

damage; posterior uveitis with focal choroidoretinitis, almostalways from congenital infection; Paul-Bunnell negative"glandular fever"; and unexplained lymphadenopathy.Diagnosis is based on assay of specific antibody in the serum,for which we now have an impressive battery oftests,3 amongwhich the dye test of Sabin and Feldman4 remains pre-eminent. The others include an indirect haemagglutinationtest,s indirect fluorescent antibody test,6 complementfixation test/ latex agglutination test,8 and the direct

agglutination test.9 To these have been added antitoxoplasrnaIgM tests with increasing specificity." In practice severaltests are usually performed and their interpretationreinforced by recourse to the dye test and IgM assay whenneccessary.3 Sometimes diagnosis is made by histologicalexamination of an excised lymph gland: Hodgkin’s diseaseand other lymphoid malignancies are not infrequentlyassociated with active toxoplasmosis. Rarely is an attemptmade to isolate the parasite by inoculation into mice. Afterprimary infection, encysted protozoa remain viable for yearsin the brain and skeletal and cardiac muscles, where, likemany other intracellular "sleepers", they are apparentlyunnoticed by us, their hosts, unless the balance betweenparasite and immunosurveillance is disturbed. -

To the four usual indications for diagnostic activity wemust now add suspected infection associated with immuno-deficiency. Therapeutic immunosuppression can permitreactivation of toxoplasma-instances have been reportedafter renal,1l liver,12 and heart transplantation13-but thisinfection tends to receive little attention among the welter ofassociated infections in these patients except when

generalised, with or without involvement of the centralnervous system ("the site of predilection"). 14 In the acquired

1. Fleck DG. Toxoplasmosis. Publ Health Lond 1969; 83: 131-352 Feldman HA. Epidemiology of toxoplasma infection Epidemiol Rev 1982; 4: 204-133 Fleck DG, Kwantes W. The laboratory diagnosis of toxoplasmosis. (PHLS Monograph

no 13) London: HMSO, 1980.4 Sabin AB, Feldman HA. Dyes as microchemical indicators of new immunity

phenomena affecting protozoan parasite (toxoplasma) Science 1948, 108: 660-63.5. Jacobs L, Lunde MN. A haemagglutination test for toxoplasmosis. J Parasitol 1957,

43: 308-14.6 Kelen AE, Ayllon-Leindl L, Labzoffsky NA. Indirect fluorescent antibody method m

serodiagnosis of toxoplasmosis. Can J Microbiol 1962, 8: 545-54.7. Warren J, Russ SB. Cultivation of toxoplasma in embryonated eggs: antigen derived

from chorioallantoic membrane. Proc Soc Exp Biol Med 1948; 67: 85-89.8. Tsubota N, Hiroaka K, Sawada Y, Watanabe T, Oshima S. Studies on latex

agglutination test for toxoplasma.(2) Evaluation of the microtitre test as a serologictest for toxoplasmosis in man. Japanese J Parasitol 1977; 26: 286-90

9 Desmonts G, Remington JS. Direct agglutination test for diagnosis of toxoplasmainfection. J Clin Microbiol 1980; 11: 562-68.

10 Payne RA, Isaac M, Francis JM. Enzyme-linked immunosorbent assay (ELISA) usingantibody class capture for the detection of antitoxoplasma IgM. J Clin Pathol 1982;35: 892-96

11. Reynolds ES, Walls KW, Pfeiffer RI Generalized toxoplasmosis following renaltransplantation. Arch Intern Med 1966, 118: 401-05.

12. Anthony CW. Disseminated toxoplasmosis in liver transplant patient. J Am MedWomen Assoc 1972; 27: 601-03.

13. Stmson EB, Bieber CP, Griepp RB, et al Infectious complications following cardiactransplantation in man. Ann Intern Med 1971, 74: 22-36

14. Ruskin J, Remington JS. Toxoplasmosis in the compromised host Ann Intern Med1982, 84: 193-99.

immunodeficiency syndrome (AIDS) serological methods fordiagnosis of reactivated toxoplasmosis have givendismayingly poor results; and the gloom has been enhancedby realisation that central nervous manifestations such ashemiparesis, seizures, and decreased consciousness mayactually be the presenting symptoms of AIDS, as they were in2 of the 7 New York patients studied by Wong et al.I5 Theseworkers found diagnostically high titres of specific IgG (dyetest or immunofluorescence test 1 in 1024 or greater) in only 3of 6 patients tested and none had specific IgM. LikewiseMcCabe et al16 obtained positive dye tests in only 12 of their38 infected AIDS patients, rises in titre were rare, and only 2had detectable IgM.These observations confirm and extend earlier reports"-"

and lead to a comparison with the infected chickens of CostaRica20 and Scandinavia,21 from which toxoplasmas werereadily isolated despite negative dye and complement fixationtests. Unlike the chickens, which possessed a competent cell-mediated mechanism to clear their bloodstream, the AIDSpatients were unable to help themselves. The reason for theirapparently poor serological response is unclear. Specific IgMmay not always appear with reactivated infections-for

instance, only 6 of 13 immunosuppressed renal transplantpatients in Glasgow with reactivated cytomegalovirus (CMV)infection had CMV-specific IgM22 and the specific IgGresponse can be low in reactivated CMV. The ability of AIDSpatients to produce IgG does not seem to be greatly impaired;indeed, Malebranche et al23 found increased concentrationsin Haitians and their complement levels were normal. Norhas selective IgG depletion been noted in adults with AIDS,although it is reported in children.24 Perhaps there is somequalitative change in the toxoplasma antibody, since McCabeet al 16 found surprisingly high direct agglutination titres-in12 of the 16 patients they were at least 20-fold higher thanthose in the dye test whereas usually they are not more than10-fold higher. This observation may provide a useful

diagnostic lever and will supplement other approaches, forsome AIDS patients with toxoplasmosis do have a diagnosticincrease of antibody in serum and cerebrospinal fluid.

Unfortunately, in central-nervous-system toxoplasmosiscomputerised tomographic scans show changes that cannotbe designated as specific, the cerebrospinal fluid is not veryabnormal, and open brain biopsy, thought helpful, is unlikelyto be an early diagnostic technique. Pyrimethamine andsulphadiazine in combination are known to be effective

against T gondii and there was some improvement, albeittransient, in 4 of the 5 patients so treated by Wong et al. 15

15. Wong B, Gold JWM, Brown AE, et al Central-nervous-system toxoplasmosis inhomosexual men and parenteral drug abusers. Ann Intern Med 1984; 100: 36-42

16 McCabe RE, Gibbons D, Brookes RG, Luft BJ, Remington JS. Agglutination test fordiagnosis of toxoplasmosis in AIDS. Lancet 1983; ii: 680

17 Rutsaert J, Melot C, Ectors M, et al. Complications infectieuses pulmonaires etneurologique d’un sarcome de Kaposi. Ann Anat Pathol (Paris) 1980; 25: 125-38.

18. Hauser WE, Luft BJ, Conley FK, Remington JS. Central-nervous-systemtoxoplasmosis in homosexual and heterosexual adults. New Engl J Med 1982; 307:498-99

19 Luft BJ, Conley FK, Remington JS, et al Outbreak of central-nervous-systemtoxoplasmosis in western Europe and North America Lancet 1983; i: 781-84.

20 Ruiz A, Frenkel JK Intermediate and transport hosts of Toxoplasma gondii in CostaRica Am J Trop Med Hyg 1980, 29: 1161-66

21 Erichsen S, Harboe A Toxoplasmosis in chickens. Acta Pathol Microbiol Scand 1954;35: 495-502.

22. Sutherland S, Briggs JD. The detection of antibodies to cytomegalovirus in the sera ofrenal transplant patients by an IgM antibody capture assay. J Med Virol 1983; 11:147-59.

23. Malebranche R, Guerin JM, Laroche AC, Elie R, et al Acquired immunodeficiencysyndrome with severe gastrointestinal manifestations in Haiti Lancet 1983; ii:

873-77.

24. Church JA, Lewis JL, Spotkov JM. IgG subclass deficiencies in children with AIDS.Lancet 1984; i: 279

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That treatment would eliminate viable cysts and so preventthe re-emergence of trophozoites in the presence of AIDSseems very unlikely. Once the diagnosis is confirmed, or evensuspected, treatment is likely to be only palliative until themultiple other horrors of AIDS can be effectively countered.

EMPYEMA OF THE GALLBLADDER— A FORGOTTEN DISEASE

THE dangers of empyema of the gallbladder were pointedout by Moynihan in 1905,1 but nowadays the condition isseldom discussed. For 1982 Index Medicus lists only onepaper inxnglish on the subject. Is this because empyema isless common or less dangerous since the advent of antibiotics?Is it because there is confusion about the exact definition? Oris it merely because there seems nothing new to be said?Empyema of the gallbladder should be defined as a

gallbladder containing frank pus with obstruction of thecystic duct. This distinguishes it from a mucocele and fromcommon acute cholecystitis. Thornton and colleagues2 havelately drawn attention to this disease and pointed out thedangers of missing the diagnosis. They found 32 cases (2’ 4%)out of 1327 patients with gallbladder disease over 5 years atthe Bristol Royal Infirmary. The average age was 71 yearsand physical signs, apart from right hypochondrialtenderness, were often absent, less than half the patientshaving a pyrexia over 37’5°C. In a quarter of the cases,abdominal pain had been present for over a month. Themortality was 25%, the major cause of death beingsepticaemia.Fry and colleagues3 recorded empyema as a complication of

acute cholecystitis and found 34 cases, with an average age of63 years, among 308 patients undergoing cholecystectomy;half the patients had no symptoms pointing to an acuteepisode, and, in 11 having routine elective cholecystectomy,empyema was totally unsuspected. The gallbladder hadperforated in 10 of the 34 patients and the operative mortalitywas 15%.North American surgeons have often stressed the dangers

of acute cholecystitis in the elderly and favour earlycholecystectomy to prevent septicaemia and the complicationof empyema or perforation. Obstacles to good management ofempyema as a whole are lack of awareness that it can be

chronic, difficulty in confirming the diagnosis, and

controversy about the correct operation. Blood cultures maygrow a mixed group of aerobic bacteria and in the elderlypatient with septicaemia or pyrexia empyema is one of thepossibilities to be excluded. Ultrasound scanning will usuallyshow a dilated gallbladder with a stone blocking the cysticduct, but it cannot distinguish between a mucocele andempyema.Once a distended gallbladder with blocked cystic duct has

been diagnosed in an elderly patient, antibiotics should begiven even if fever is absent. The clinical course should becarefully monitored and if there is no ultrasound evidence ofresolution or if signs of septicaemia appear, urgent operationis advisable. Sometimes cholecystectomy can be donewithout opening of the gallbladder, but if the surroundinginflammation is extensive and the patient’s general condition

1. Moynihan BGA. Gall-stones and their surgical treatment. Philadelphia W.B.Saunders, 1905: 196.

2. Thornton JR, Heaton KW, Espiner HJ, Eltringham WK Empyema of the gallbladder-reappraisal of a neglected disease. Gut 1983; 24: 1183-85

3. Fry DE, Cox RA, Harbrecht PJ. Empyema of the gallbladder: a complication in thenatural history of acute cholecystitis. Am J Surg 1981; 141: 366-69.

is poor, drainage cholecystostomy is the best policy. After all,the patient has a large abscess and the initial treatment of anabscess is drainage. If the stone blocking the cystic duct can beremoved at the same time, further elective surgery may beavoided. If the cystic duct is still blocked ten days later whenthe gallbladder is X-rayed (with contrast medium introducedthrough the drainage tube) simple removal of the drain maylead to intermittent mucous discharge over the followingmonths or years. Sometimes, however, the mucosa has beencompletely destroyed and the gallbladder becomes a fibrouscord. Exploration of the common bileduct in the presence ofan empyema carries a high morbidity3 and should be doneonly if operative cholangiography shows clear evidence of astone likely to block the duct. If in doubt, the surgeon shouldbe content to drain the pus and reoperate later or use

endoscopic techniques, when the patient is over this life-threatening emergency.

PERCUTANEOUS ANGIOPLASTY FOR PERIPHERALVASCULAR DISEASE

IN the ten years since Gruntzig’ described his double-lumen catheter for relieving stenosis of peripheral arteries,percutaneous angioplasty has emerged as an attractive,simple alternative to aortofemoral and femoropoplitealbypass in the treatment of intermittent claudication andischaemic rest pain.2 Doubilet and Abrams,3 from Boston,have lately analysed the published results from 1970 to 1981of treatment of more than 5000 ischaemic lower limbs bythree methods-angioplasty alone, surgery alone, andangioplasty followed by-surgery if the initial angioplasty wasunsuccessful or the vessel became occluded later ("combinedapproach"). Various sorts of operation are examined, but acomparison of angioplasty and femoropopliteal surgery gavetypical results-cost$2585 versus$13 970; mortality rate forthe procedure 0 17% versus 2 - 6%; complication rate 2 - 3%versus 6-7%; and five-year patency rate 29-4% versus

59-9%. The last figure, therefore, partly offsets the

advantages of angioplasty in terms of mortality,complications, and cost. The best outcome was obtained withthe combined approach, which gave the most patent limbs atfive years and, because many patients did not require a bypassoperation, still cost a little less than the surgery-only policy.

In the United States in 1980, only 6-7% of arterialoperations for peripheral vascular disease were percutaneousangioplasties, and Doubilet and Abrams believe that thisproportion ought to be nearer 40%. Dissemination of

angioplasty has been delayed, they say, because vascularsurgeons have been slow to recognise its merits and becausesurgeons suffer financially when they refer a patient to aradiologist rather than operating themselves. Systems such asthe British National Health Service are free from personalfinancial pressures of this sort, but Doubilet and Abrams’best buy-angioplasty and surgery-will uncomfortablystraddle the budgets of the divisions of radiology and surgery.At a time when vascular surgeons are increasingly referringpatients for interventional radiology, we need the kind ofdetailed specialty costing that has been done for cardiacsurgery,4 to assist judgments on this mode of treatment.

1. Gruntzig A, Hopff H. Perkutane Rekanalisation chronischer arteriellar Vershlusse miteinen neuen Dilationikatheter. Dt Med Wschr 1974; 99: 2502-05.

2. Campbell WB, Jeans WD, Cole SEA, Baird RN Percutaneous transluminal

angioplasty for lower limb ischaemia. Br J Surg 1983, 70: 736-39.3 Doubilet P, Abrams HL The cost of underutilization. Percutaneous transluminal

angioplasty for peripheral vascular disease. N Engl J Med 1984, 310: 95-102.4. Mollo S. Speciality costing. Health Soc Serv J 1982; 92: 339-41.