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successful treatment of two bone marrow transplant (BMT)recipients with CMV pneumonitis. The diagnosis was wellestablished by bronchoscopic sampling, and both respondedwell to a 15-day course of intravenous foscarnet. It is evidentin a later report by Blacklock et als that one of these patientsrelapsed and was then treated successfully with specifichyperimmune globulin. Ringden and colleagues reporteduse of the drug in 35 transplant recipients with less

impressive results. All nine BMT recipients with CMVpneumonitis died. Better results were apparently obtained inrenal transplant patients with pancytopenia, fever, and otherconditions. This report cannot, however, be evaluatedwithout knowledge of the site of isolation of the positivecultures. Many immunocompromised patients excrete

CMV, and demonstration of virus in the chest is essential fora definitive diagnosis of CMV pneumonitis.Sandstrom and colleagues have lately reported inhibition

of HTLV III/LAV in vitro by foscarnet. The reverse

transcriptase activity in purified virus particles was

completely inhibited by 5.0 µmol/l but 680 µmol/l wasrequired to block replication of the virus in cell culture.Preliminary data indicated that the virus was not reactivatedafter withdrawal of this concentration. CMV is known tobecome latent and HTLV III/LAV also seems to persist.Foscarnet is a virostatic agent that seems to have some effecton severe CMV infection and has activity against HTLVIII/LAV in vitro. The drug must be given by continuousintravenous infusion because of its short half-life in plasmaand only small amounts enter the brain tissue. It may have aplace in the treatment of severe CMV infection if the immuneresponses are able to recover and prevent relapse, but theneed for intravenous therapy makes it unsuitable for long-term maintenance. This drawback is also likely to hamperassessment of this agent in the early clinical stages of HTLVIII/LAV infection.

XANTHOGRANULOMATOUS PYELONEPHRITIS

THE pathological features of xanthogranulomatouspyelonephritis (XPN) were described by Schlagenhaufer8 in1916 and later by Putschar,9 the term "xanthogranulomatouspyelonephritis" being suggested by 0sterlind 10 in 1944.

Since then, some 500 cases have been published, most ofthem in adults,II,12 with some in children.13,14 XPN is amorphological variant of pyelonephritis characterised by theacumulation of large numbers of lipid-laden macrophages ininflamed and often suppurating areas of renal tissue. Thesolid areas of closely packed foamy macrophages seen in somestages of XPN can be mistaken for the clear cells of renalcarcinoma. XPN usually affects the renal pelvis and calyces,

5. Blacklock HA, Griffiths P, Stirk P, Prentice HG. Specific hyperimmune globulin forcytomegalovirus pneumonitis Lancet 1985; ii 152-53.

6 Ringdén O, Wilczek H, Lonnqvist B, et al. Foscarnet for cytomegalovirus infections,Lancet 1985; ii 1503-04.

7 Sandstrom EG, Byington RE, Kaplan JC, Hirsch MS. Inhibition of human T-celllymphotropic virus type III in vitro by phosphonoformate. Lancet 1985; ii:1480-82

8 Schlagenhaufer F. Uber eigentumliche staphlomykosen der Nieren und des paranalenBindegewebes. Z Pathol 1916, 19: 139-48.

9. Putschar W. Die entzundlichen Erkran kungen der ableitenden Harnwege und derNieren hüllen einschliesslich der Pyelonephritis und der Pyonephrost. In: Henke F,Lubarsch O, eds. Handbuch der Speciellen Pathologlschen Anatomie undHistologie: vol VI. Berlin Springer, 1934. 333-564.

10 Østerlind S. Uber pyelonephritis xanthromatosa. Acta Chir Scand 1944; 90: 369-76.11. McDonald GSA. Xanthogranulomatous pyelonephritis. J Pathol 1981; 133: 203-13.12. Grainger RG, Longstaff AJ, Parsons MA. Xanthogranulamatous pyelonephritis: a

reappraisal. Lancet 1982; i: 1398-140113. Yazaki T, Tshikawa S, Ogawa Y, Takahashi S, Nemoto S, Rinsho K, Kanoh S,

Kitagawa R Xanthogranulomatous pyelonephritis in childhood: case report andreview of English and Japanese literature J Urol 1982; 127: 80-83.

14. Kierce F, Carroll R, Guiney EJ. Xanthogranulomatous pyelonephritis in childhood.Br J Urol 1985; 57: 261-64

and xanthogranulomatous areas are visible macroscopically.One of the important and least recognised complications ofXPN is the ability of the condition to extend into perinephric,tissue, with a high proportion of perinephric abscesses. Sinusformation may extend in any direction within the abdomen orabdominal wall. Fistulae may develop to affect the small orlarge bowel or extend to the skin in the loin or in moreunusual sites, such as the buttock, axilla, chest, or groin.ls,16This progressive infiltrating granulomatous reaction

develops as a complication of prolonged, usually low-gradesuppuration in a kidney in which the flow of urine isobstructed. The obstruction is most often due to calculusdisease (76%) and less often to other abnormalities affectingthe pelviureteric junction (18%) and rarely to other lesionssuch as ureteric tumour.12 Proteus mirabilis and Escherichiacoli are the most common infecting organisms.

Clinically the typical XPN patient is a middle-aged womanwith severe toxaemia and weight loss, anaemia, and a higherythrocyte sedimentation rate, pyrexia of uncertain origin, andmild lower urinary-tract symptoms. Loin pain, tenderness, ora mass in the loin should alert the clinician to the possibility ofXPN. The condition can occur, albeit rarely, in children,13,14the youngest patient described being 2 years old. Again, renalcalculus disease with obstruction occurs in the vast majorityof cases in children, and the clinical signs and investigativefindings are similar to those in adults. Conventional

radiography of the abdomen often reveals calculus of theurinary tract, usually of the staghorn type. The affectedkidney is sometimes enlarged and the outline ill-definedbecause of perinephric oedema or infiltration. Loss of surfaceoutline is not a reliable sign, even of perinephric abscess.Intravenous urography reveals absent function of the affectedkidney in some 80% of patients, with reduced function in theremainder, distortion of calyces and hydrocalycosis beingevident when renal function is adequate for visualisation.Ultrasonography shows sonolucent areas due to distendedcalyces, and echogenic areas due to the solid foci of

granulomatous tissue, as well as debris and calculi in some ofthe renal cavities. Computerised tomography usually revealsthe extent of perirenal involvement, as well as the details ofintrarenal lesions-calculi, renal destruction, hydronephrosis,and abscess formation. Because the condition may mimic theclinical, radiological, and histological features of renal

tumours, in particular renal carcinoma, 15,16 selective

arteriography is sometimes done. This usually shows

splaying of the intrarenal branches stretched aroundavascular zones with some patients having a very disorderedintrarenal arterial pattern resembling the neovascularity ofhypernephroma; but, unlike tumour blood vessels, theintrarenal arteries in XPN contract to adrenaline challenge.Renal capsular arteries are often enlarged and extend into theperirenal tissue. Retrograde pyelography usually revealshydronephrosis and the level of obstruction but does not helpin differentiating XPN from a neoplasm. Percutaneous

biopsy of the affected area plays little or no part in the

diagnosis and carries the risk of spread of infection and sinusformation.Parsons et al17 have proposed pathogenetic mechanisms in

XPN in which a kidney with obstructed urinary outflow

15. Malek RS, Elder JS Xanthogranulomatous pyelonephritis a critical analysis of 26cases and the literature. J Urol 1978; 119: 589-93.

16 Tolia BM, Iloreta A, Freed SZ, Fruchtman B, Bennett B, Newman HRXanthogranulomatous pyelonephritis. Detailed analysis of 29 cases and a briefdiscussion of atypical presentations J Urol 1981, 126: 437-42

17. Parsons MA, Harris SC, Longstaff AJ, Grainger RG. Xanthogranulomatouspyelonephritis, a pathological, clinical and aetiological analysis of 87 cases

Diagnostic Histopathol 1983; 6: 203-19.

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becomes prone to ascending urinary tract infection provokingacute pyelitis without, at first, the inflammatory infiltratepenetrating the pelviureteric transitional epithelium or

significantly affecting the renal medulla. Increasing oedemamay further obstruct urinary outflow, and as theinflammation increases the pelviureteric epithelium becomesulcerated and the process extends into the renal medulla and

pericalyceal fat, with necrosis of the pericalyceal fat andrelease of free lipid. Because the kidney is obstructed necroticinflammatory debris and lipid cannot drain away via the ureter and the accumulated fat undergoes phagocytosis byinfiltrating macrophages. The macrophages become packedwith fat droplets and assume the histological appearance ofxanthoma cells. In Parsons and colleagues’ scheme, pus andmacrophages (xanthoma cells) accumulate as the oedemaincreases. "With time, organisation of the inflammatoryprocess begins, with capillaries extending into necrotictissue. The predominantly inflammatory cells tend to changefrom the neutrophil polymorph to the lymphocytes.Meanwhile, xanthoma cells accumulate around capillaries,form solid masses separated by numerous capillaries andeventually elongate into a spindle-shaped configuration withincreasing fibrosis. Failure of drainage of the inflammatoryinfiltrate in the acute phase may lead to the commonextrarenal extension (or ’pointing’) of XPN, with formationof perinephric abscesses or, more rarely, sinus or fistuladraining into organs such as the large bowel."Renal neoplasms, especially renal cell carcinoma, may be

difficult to distinguish clinically from XPN-indeed thesurgical, pathological, and histological findings may also bevery similar. However, the presence of calculus disease withobstruction, in a toxic and anaemic patient, makes XPN themore likely, especially in the presence of a perinephricabscess. Unusually the patients may have few, if any,urological symptoms. The treatment is not prolongedantibiotic therapy or drainage of a presumptive pyonephrosisor perinephric abscess, which will lead to persistent orrecurrent sinus or fistula formation. Total or partialnephrectomy is the only method of cure.

INFANT MORTALITY AND FAMILY STRUCTURE

THE overall mortality among the population of Englandand Wales, allowing for changes in age structure, has declinedcontinuously since accurate records became available in themiddle of the 19th century. Moreover, there is good reason tobelieve that mortality began falling at least 150 years earlier.The reduction in total mortality is almost entirelyattributable to the decline in deaths from infectious diseases.When Victorian sanitary engineering separated drinkingwater from sewage, enteric diseases fell in prominence; themechanism of control in this instance is obvious-lessening ofrisk of exposure to pathogens. The reason for the decline indeaths from airborne diseases is more difficult to establish,but McKeown’ has argued that it is due to increased hostresistance resulting from a general improvement in nutrition.For tuberculosis and scarlet fever, however, there is suspicionthat the pathogenicity of the organisms has diminishedand/or that selective effects may have reduced the geneticsusceptibility of the population.But when one examines age-specific rather than overall

mortality an anomaly is immediately apparent. For peopleaged between 5 and 45 years there was a steady fall in all

1. McKeown T The role of medicine-dream, mirage, or nemesis? London: NuffieldProvincial Hospitals Trust, 1976

causes of mortality from 1841 onwards, while for olderpeople the decline, as might be expected, was less rapid. Yetmortality for those under 5 years of age did not start to declineuntil the turn of the century; thereafter it was rapid. Thisobservation was the starting point for an epidemiologicalinquiry by Reves.2 He felt that McKeown’s nutritional

hypothesis did not explain the pattern of infant mortalitybecause the benefits of improved nutrition should showsimultaneously in all age groups. Furthermore, the benefitfrom control of enteric disease should have manifested itselfin the infant population long before the turn of the century.Reves’ hypothesis is that a decline in fertility in the late

1800s was largely responsible for the decline in infant

mortality that began in 1900. This was brought about by analteration of family sizes and distribution of ages withinfamilies. Thus the average age of contracting infectiousdiseases was raised, thereby lowering the case-fatality rate.This hypothesis is biologically plausible and the decline infertility is well established. The fall in fertility also correlateswell with the decline in infant mortality, but more directevidence is desirable. Regrettably, only recently have

demographic data been gathered that would allow such ahypothesis to be examined directly. So, in attempting to studymortality by family structure in the 19th century, Reves wasforced to tackle the problem tangentially and herein lies muchof the attraction of his paper: it is a case study of theintellectual rewards of epidemiological inquiry.In essence, Reves used indirect standardisation, applying

infant mortality statistics, by cause and maternal parity, fromthe 1949-50 cohort study3 to estimated distributions ofbirths by birth order between the years 1871 and 1931.Distributions of births by birth order were calculated fromperiod fertility rates by use of data about various marriagecohorts going back to 1886. For bronchitis and pneumonia heobtained a pattern of expected deaths rates between 1871 and1931 that parallels the actual death rates, although themagnitudes, as would be anticipated, are very different.Nevertheless, he was able to reproduce the anomalous shapeof the trend, changes in family structure influencing theaverage age of exposure to infection seem to account for theobserved pattern. Independent supporting evidence wasgained by examining the distribution of deaths by age frommeasles between 1901 and 1930. This shows a reduction overtime in infant and childhood deaths and an increase in the

average age at death. If we assume that death rates are

proportional to the risk of infection, and hence to the risk ofexposure, then these findings accord with the view that theaverage age at exposure has increased.The validity of Reves’ assumptions and calculations will be

subject to discussion, but he has established a plausible caseand in many ways his arguments are better supported thanthe rather vague nutritional hypothesis. However, this work,if generally accepted, should be seen as embellishing ratherthan contradicting McKeown’s thesis. Indeed it does notundermine the notion that improvements in nutrition andliving conditions explain much of the improvement in healthsince the early 18th century; McKeown’s argument that themajor improvements in health are attributable to changes insocial conditions and sanitation rather than to the prowess ofcurative medicine remains undamaged.

2. Reves R. Declining fertility in England and Wales as a major cause of the twentiethcentury decline in mortality. The role of changing family size and age structure ininfectious disease mortality in infancy. Am Epidemiol 1985; 122: 112-26.

3. Heady JA, Heasman MA. Social and biologic factors in infant mortality GeneralRegister Office. (Studies on medical and population subjects, no 15.) London- HMStationery Office, 1958.