Genitourin Med. 1991;67:156-161

Clinico-pathological conference

Complications of treatmentfor cryptosporidialdiarrhoea

J Anderson, R J D George, I V D Weller, S B Lucas, R F Miller

Case report (Dr Jane Anderson)A 26 year old Caucasian, homosexual, male civilservant was found to be HIV antibody positive inNovember 1988. At that time he reported weightloss, night sweats and a scaling rash over the face andneck. On examination he was thin and weighed 67 kg.He had cervical and axillary lymphadenopathy and a

crusting facial rash, and hairy oral leucoplakia. Thehaemoglobin was 15 9 g/dl, total lymphocyte count1 5 x 10'/1; a chest radiograph was normal. He was

p24 antigen negative. He had no markers of hepatitisB infection despite having had a full course ofhepatitis B vaccine in 1986. He was given aqueouscream, Canesten HC (clotrimazole 1% and hydro-cortisone 1 %) cream and minocycline with goodresults.Three weeks later he re-presented with a four day

history of cramping abdominal pain and episodicwatery, blood-free diarrhoea; cryptosporidium was

isolated from the stool. Symptoms persisted over thenext five weeks and further stool samples were

positive for cryptosporidia. At that point the alkalinephosphatase had risen to 309 IU/l (normal < 28 IU/1) and theAST was elevated at 102 IU/l (normal < 35IU/1). The other liver function tests, haemoglobinand electrolytes were normal. Oral erythromycin 500mg qds and loperamide were prescribed. Within twodays his condition deteriorated and he was admittedto hospital with constant abdominal pain and 15-20stools per day. Cryptosporidium was again isolated

Department of Genitourinary Medicine, MiddlesexHospitalJ AndersonDepartment ofMedicineR J D GeorgeR F MillerAcademic Department of Genitourinary.MedicineI V D WellerDepartment of HistopathologyS B LucasUniversity College and Middlesex School ofMedicine, Middlesex Hospital

from the stool. The erythromycin was discontinuedand his symptoms improved gradually. Zidovudinewas introduced at a dose of 250 mg qds and he wasdischarged.Within four days he was readmitted with vomiting

and diarrhoea together with oral candidiasis, and hewas unable to eat. Zidovudine was discontinued andhe was given liquid food supplements which hetolerated poorly. Several attempts were made to passa naso-gastric feeding tube without success.Symptom control was achieved with subcutaneousdiamorphine, cyclizine and hyoscine via a syringepump driver. His diarrhoea settled and his vomitingwas very much improved. Fluconazole was given forthe oral candidiasis and zidovudine was reintroducedat a dose of 100 mg tds, which he tolerated. He waseventually discharged on MST Continus (morphinesulphate sustained release) and oral cyclizine.Over the next four months he was followed up as an

outpatient. He had occasional episodes ofnausea andvomiting but very little diarrhoea. Liver functiontests returned to normal. Multiple stool culturesremained positive for cryptosporidia and he was ableto tolerate zidovudine at a dose of 250 mg qds, andcontinued on MST Continus. He used metoclo-pramide and fluconazole intermittently. Towards theend of this period his alkaline phosphatase had risento 580 IU/l and the AST to 54 IU/l. The other liverfunction tests and an abdominal ultrasound werenormal. Over the next six weeks he developed rightupper quadrant pain exacerbated by eating. Furtherstool cultures were positive for cryptosporidium. Hewas given oral spiramycin; despite this hedeteriorated and was readmitted with increasingright upper quadrant pain and vomiting, but hisdiarrhoea was well controlled. Liver function testsshowed a further deterioration with an alkalinephosphatase of 708 IU/l and an AST of 114 IU/l.A repeat abdominal ultrasound showed marginalenlargement of the liver and spleen. He was givenranitidine and metoclopramide; subcutaneousdiamorphine was reintroduced to control hissymptoms and he continued on full-dose zidovudine.

156

on Novem

ber 18, 2020 by guest. Protected by copyright.

http://sti.bmj.com

/G

enitourin Med: first published as 10.1136/sti.67.2.156 on 1 A

pril 1991. Dow

nloaded from

Clinico-pathological conference: complications of treatmentfor cryptosporidial diarrhoea

Fig I Endoscopic retrograde cholangio-pancreatogramshowing dilatation of the common bile duct and multipleirregularities of the intrahepatic ducts.

Dr R F MillerEndoscopic retrograde cholangio-pancreatography(ERCP) showed dilatation of the common bile ductwith irregular mucosa throughout the biliary tree andmultiple irregular intrahepatic strictures (fig 1). Thiswas consistent with sclerosing cholangitis and asphincterotomy was performed, which reduced hispain but the alkaline phosphatase andAST remainedgrossly elevated.

Dr J AndersonOn discharge from hospital he was managed at homeby the Bloomsbury Community Care Team. Hecontinued to have diarrhoea, nausea and vomitingwhich were controlled with metoclopramide,cyclizine and dexamethasone. Several weeks later hedeteriorated and required hospital admission. Hewas passing 2-3 litres/day of diarrhoea and wasvomiting. The liver was found to be smoothlyenlarged four fingers breadth below the costalmargin. The alkaline phosphatase was 945 IU/land AST 98 IU/l. Abdominal ultrasound showedan enlarged liver with a dilated common bile ductand intrahepatic ducts consistent with sclerosingcholangitis.His course in hospital was complicated by a

Haemophilus influenzae chest infection. A Hickmanline was inserted and total parenteral nutrition

(TPN) was instituted. This was complicated by aStaphylococcus aureus infection at the Hickman lineentry site on the chest wall; the blood cultures takenthrough the line and from peripheral sites werenegative. He was treated with flucloxacillin with goodresults. Spiramycin given simultaneously by oral andintravenous administration was tried in an attempt tocontrol the cryptosporidial diarrhoea. This madelittle impact on his symptoms. Somatostatinanalogue was tried in an attempt to control thediarrhoea without benefit.Over the last 2 months of his life he was managed

entirely at home and continued to receive TPN,supervised by the Community Care Team.Zidovudine was discontinued but he remained ondiamorphine, hyoscine, dexamethasone, metoclo-pramide and fluconazole. He developed a generalisedred macular rash after 2 months on TPN. Terminallyhe developed polyarthralgia with particularinvolvement of the left shoulder, a broncho-pneumonia and pulmonary oedema. He died 14months after his original presentation with crypto-sporidial diarrhoea.

Discussion (Dr R J D George)It may seem rather strange for a palliative physicianto be managing somebody at home, at the end of theirlife, with something as "aggressive" as parenteralnutrition. From the patient's point of view, while hewas aware ofprognosis, the indications justifying thiswere as follows: both he and his family wanted him tospend his last weeks at home, and there were severalimportant issues to resolve conceming his personalrelationships and spiritual integration. To be wellenough to deal with these things at home was hisabsolute priority. From our point of view, to achievethese endpoints, he needed aggressive symptomcontrol. He was unable to tolerate oral fluid, and wasseverely malnourished and dehydrated. TPN

40

30

20

10

...................I.................ERCP TPN :: ::::::.,

I........... .........................

I IHICKM HME

1 -2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17Weeks i are of teem

Fig 2 Support Team Assessment Schedule (STAS) scorefor the patient during his care by the Bloomsbury CommunityCare Team. Following insertion ofa Hickman line andinstitution of Total Prenteral Nutrition ( TPN) there was amarkedfall in the STAS score.

t'i

157

on Novem

ber 18, 2020 by guest. Protected by copyright.

http://sti.bmj.com

/G

enitourin Med: first published as 10.1136/sti.67.2.156 on 1 A

pril 1991. Dow

nloaded from

Anderson, George, Weller, Lucas, Miller

therefore seemed justifiable as a palliative measure.We achieved these goals; TPN made a significantdifference to the quality of his life and he was able tocomplete his remaining agenda.Do we have any data to justify these statements? As

part of continuing clinical audit of team practice inthe Bloomsbury Community Care Team, we haveestablished a system which was developed to examinethe quality of life in people dying with cancer.' Thisscoring system, the Support Team AssessmentSchedule (STAS) goes beyond conventional clinicalproblems such as pain or symptom control, andquantifies patient and family anxiety and insight,communication, planning, spiritual needs and so on.Each area is scored weekly on a defined five point scaleto produce an aggregate reflecting overall quality oflife and care being given. By quantifying theseparameters, we are able both to understand and trackthe patterns and interactions of cofactors of impor-tance in clinical and psychosocial care. Figure 2shows the plot in this case. A high score is bad and thelow score is good. The message is clear. You will seethat prior to starting TPN the patient's wellbeingwas erratic and relatively poor. Poor symptom con-trol characteristically affects other things like anxietyand communication within the social structure andprecipitates crisis. The scores reflect this and had henot been admitted, the whole family setup wouldhave collapsed. At the onset of TPN the scoredropped dramatically, as the situation was contained.This stability continued to the end ofhis life when hewas scoring 1 or 2 (ie occasional symptoms, noanxiety in him or the family, full communication,spiritual peace and preparedness for death). Givenhis pathology this was probably optimum.Another area worth commenting on is the adminis-

tration ofeffective symptom control in the face ofsuchextensive pathology. In patients with overwhelminggastrointestinal symptoms, oral or rectal medicationis seldom effective because of vomiting, short guttransit times or malabsorption from mucosal dis-ruption. In these cases we have found that parenteraladministration is often necessary. Fortunately, mostdrugs (the main exceptions to this are diazepam,stemetil and chlorpromazine) can be mixed and givensubcutaneously using a pocket size syringe driverrecharged 12 or 24 hourly. Early on in his history thepatient's first severe bout of diarrhoea and vomitingwas controlled by subcutaneous diamorphine andmetoclopramide and he was then transferred success-fully to equivalent oral doses ofMST Continus andmetoclopramide. In the last 3 months of his life themajority of his medication was given by syringedriver in doses titrated against symptoms.Some drugs may also serve several purposes. The

dexamethasone was initially used for its antiemeticeffect, but later its principal value was to suppress thesystemic effects ofinfection, the diamorphine initially

controlled the diarrhoea at doses of about 200 mg/24 h but later increased successfully to 500 mg tosuppress cough and breathlessness, and the anti-cholinergic effect of hyoscine, apart from reducinggut secretion, almost certainly contributed as anantiemetic and dried up the large airway secretionsthat aggravate cough.The final point to make is that many of these

patients with severe gastrointestinal symptomsrequire combination antiemetic therapy. It is essen-tial to use adequate doses of each drug, to introducethem one at a time to maximum dose and then toselect a representative from another group if symp-toms persist. At the end of his life, this patientwas receiving 4 antiemetics subcutaneously withadditional high dose metoclopramide via hisHickman line to maintain complete control of hisvomiting.

Dr I VD WellerThis man presented with persistent generalised lym-phadenopathy and a few constitutional symptoms in1988. I note from the history he failed to respond tohepatitis B vaccine in 1986. In a study carried outhere in 1986 it was demonstrated that the response inHIV positive patients is diminished and other studieshave confirmed this.2' This may suggest that he wasalreadyHIV infected in 1986 which would fit with thedisease course. However, a small proportion ofyoung, healthy individuals do not respond tohepatitis B vaccine either.As a general comment about the case I am sur-

prised how long this man survived considering hepresented with severe cryptosporidial diarrhoea inDecember 1988. Obviously the palliative care that hereceived gave him a reasonable quality of life.One usually sees AIDS sclerosing cholangitis late

on in HIV disease.45 About 65-75% of cases in theliterature have been described in association witheither cryptosporidial or CMV infection or both.Whether these agents are passengers or pathogensremains to be seen. Other organisms are occasionallyfound such as various types of bacteria and candidabut these may well be secondary infections as a resultofthe alteration in biliary architecture and not causal.

I was a little surprised by the liver function testsreturning to normal but his symptoms and signs alsosettled during this early period. With later diseaseone sees fluctuations in liver function tests but theyrarely return to normal.There is something that worries me about this

patient and others we have managed with diarrhoealike this. Although we have found cryptosporidiumin the stool, we tend not to investigate further as far asother gastrointestinal problems are concerned. CMVdisease was not excluded in this case. Even flexiblecolonoscopy may miss CMV disease in the ascendingand transverse colon.

158

on Novem

ber 18, 2020 by guest. Protected by copyright.

http://sti.bmj.com

/G

enitourin Med: first published as 10.1136/sti.67.2.156 on 1 A

pril 1991. Dow

nloaded from

Clinico-pathological conference: complications of treatmentfor cryptosporidial diarrhoea

Moving on to the question of treatment of crypto-sporidiosis, the short answer is that there is no specifictreatment and the long answer is that a large numberof treatments have been tried and some have hadanecdotal success. I think this man was obviouslytreated during the phase when we were trying varioussorts of agents. Spiramycin and somatostatin are twoexamples of this. There are also some reports thatzidovudine may improve diarrhoea associated withcryptosporidial infection but there are no controlleddata on this. Our real problem is that we do not knowhow cryptosporidium causes diarrhoea. It is hardlyinvasive. The intermediate form ofthe parasite sits inthe intestinal cells in an intracytoplasmic position butjust on the edge covered by the cell membrane. Itmay be that it releases some form of toxin. Thediarrhoea could be mediated by gut hormones oreven the immune response to the organism andtherefore perhaps even cytokines are involved. Thesevarious possibilities are another reason why so manydifferent therapies have been tried. The other drugwhich we were trying to obtain at the time wasdiclazoril. This is an agent which is used in veterinarymedicine and is active against protozoa in chickens.Again, there have been anecdotal reports of successand a controlled trial is underway in the UnitedStates.With respect to the management ofAIDS scleros-

ing cholangitis you did a sphincterotomy because ofpain. Certainly if there is stricture at the lower end ofthe common bile duct and the patient is experiencinga lot of pain this is worth trying since there have beena number of reports now to show that this procedurecan help.4 However, it rarely helps the abnormal liverfunction tests, as one might expect, with suchwidespread both extra and intrahepatic disease.His later clinical course shortly before his death

reminded me of a number of cases we have seen ofdisseminated staphylococcal infection with pustularrashes and septic arthritides. This is particularlyrelevant with him having an indwelling intravenousline.67 Indeed, staphylococcus was isolated on oneoccasion from this and he received a short course offlucloxacillin.

In summary, in terms of the management of thisman I am sure that to concentrate on palliative carewas the most important thing to do. However,coming back to what the necropsy revealed, I returnto my comment about continuing to manage patientsover a long course once the diagnosis of crypto-sporidial disease is made, without further investigat-ing the gastrointestinal tract. So I am worried thatour pathologist might tell us that this man had eitherunderlying gastrointestinal disease due to CMV oreven perhaps a lymphoma.Clinical diagnosis: (1) Staphylococcal septicaemia

(2) Cryptosporidial diarrhoea(3) AIDS sclerosing cholangitis(4) CMV or lymphoma of gut?

Pathology (Dr S B Lucas)The macroscopic findings first. He was autopsied 4days after death and he was emaciated and jaundiced.On the skin were several brown papular seborrhoeickeratoses and a fine macular erythematous rash.The heart was large and flabby, within the muscle

numerous small white spots were visible, he had amyocarditis. There were bilateral pleural effusionsand the lungs were large, triple the normal weight.On cutting they were oedematous and broncho-pneumonic. In the gastrointestinal tract, the mouthwas normal and the tongue did not show oral hairyleucoplakia. The lower oesophagus was ulcerated.The small bowel was greatly distended with brownliquid contents; no focal lesions were seen on themucosa. The large bowel contained some brownishtoothpasty material, and again no focal mucosallesions. The liver was enlarged and green fromcholestasis. The gall bladder appeared normal; butthe common bile duct was dilated to over 1 cm indiameter and had a thick and irregular mucosa. Theampulla ofVater looked normal even though he had apapillotomy, probably because of post-mortemautolysis and muscle slackening.

(a)

(b)Fig 3 (a) Heart muscle showing multiple abscesses some ofwhich are surrounding blood vessels (magnification x 20).(b) High power view of abscess showing it to be composed ofpolymorphs. A cluster of Gram positive cocci are seen withinthe abscess (top right) (magnification x 40).

159

on Novem

ber 18, 2020 by guest. Protected by copyright.

http://sti.bmj.com

/G

enitourin Med: first published as 10.1136/sti.67.2.156 on 1 A

pril 1991. Dow

nloaded from

Anderson, George, Weller, Lucas, Miller

(a)

--,

--~~~~~~~~~~~~~~~~~~~~~~~~r

* * w t *''!j f'A - ,,o ,

Fig 4 (a) Wall of the common bile duct showing

considerable thickening. There is distortion of theglands with

acute inflammation andfibrosis (mnagnification x 10)J.(b) High power view of epithelial surface of the wall of the

comnmon bile duct showing many of the cells contain CMV

inclusions (magmification x 40).

The kidneys had widespread white spots, like the

heart. The spleen was large but appeared unremark-

able on section. Lymph nodes from different sites in

the abdomen were just a little larger than thecommon atrophic nodes found in AIDS cases, butwere non-necrotic. The thyroid was firm, and theadrenals atrophic from the steroid therapy. Exter-nally the brain appeared normal, as it did on brain-cutting after fixation. The spinal cord and eyes werenot examined.The histopathology shows that the white spots in

the kidneys and heart were abscesses containinggram-positive cocci, consistent with Staphylococcusaureus. In the heart there were abscesses under theendothelium, presumably seeding to and from theblood stream (fig 3). There was necrotisingbronchopneumonia in the lungs with focal necrosesassociated with colonies of bacteria.The atrophic adrenals also contained small bac-

terial abscesses as did the thyroid (but withoutsufficient damage to produce hypofunction). Themeninges were not inflamed, but throughout thecerebrum, cerebellum and brain stem-white andgrey matter-there were small foci of demyelinationassociated with staphylococcal abscesses. The smallarteries had necrotic walls and were obstructed bythrombus adjacent to the staphylococcal colonies. Bycalculation there were up to fifty thousand of thesesmall abscesses within his brain, surprisingly, as hewas said to be mentally normal just before death;probably these abscesses developed terminally.On the skin, apart from some molluscum con-

tagiosum lesions, the macular rash was due to focalischaemic lesions caused by staphylococcal pyaemiain the mid and upper dermal blood vessels, causingthrombosis. In some areas the epidermis had smallvesicles containing colonies of Staphylococcus.The oesophageal ulceration was not due to CMV

or candidiasis, but-again-was caused by sta-phylococcal pyaemia with infarcted epithelium. Des-pite the autolysis, the mucosa of the entire small andlarge bowel was acutely inflamed with polymorphs,associated with numerous CMV inclusions in theendothelium and lamina propria. No cryptosp-oridium was evident, but that parasite rapidly disap-pears from gut mucosa after death, so post-mortemhistology usually cannot help assess its extent unlessautopsy is performed within a few hours of death.The liver parenchyma was cholestatic with

numerous small bile plugs indicating duct obstruc-tion; in the peripheral part sampled the portal tractsare normal without evidence of sclerosing cholan-gitis. Possibly the liver nearer the hilum may haveshown more abnormalities. The wall of the commonbile duct was double the normal thickness and wasinflamed and fibrosed. The glands were distorted byacute inflammation and fibrosis (fig 4). This was activesclerosing cholangitis. Some of the epithelial cellscontained CMV inclusions, but no cryptosporidiumcould be seen. They may have been present, butautolysis has occurred.

160

on Novem

ber 18, 2020 by guest. Protected by copyright.

http://sti.bmj.com

/G

enitourin Med: first published as 10.1136/sti.67.2.156 on 1 A

pril 1991. Dow

nloaded from

Clinico-pathological conference: complications of treatment for cryptosporidial diarrhoea

To summarise, the actual causes of death in thisman were bronchopneumonia and heart failure dueto staphylococcal septicaemia. He also had sclerosingcholangitis and CMV enteritis; cryptosporidialenteric infection was diagnosed during life. As acause of death, staphylococcal septicaemia isrelatively uncommon in most series of AIDS postmortems.89

Pathological diagnoses:1. Staphylococcal septicaemia, with cerebral, car-

diac, pulmonary, cutaneous, oesophageal andendocrine abscesses.

2. CMV enteritis.3. Sclerosing cholangitis associated with CMV

infection.

Address for correspondence: Dr R F Miller,Department of Medicine, 5th Floor, Jules ThornBuilding, UCMSM, Middlesex Hospital, London,WIN 8AA, UK.

1 Higginson IJ, Wade A, McCarthy M. The Support TeamAssessment Schedule: A Measure for Outcome of PalliativeCare. J Clin Epidemiology 1991 (in press).

2 Carne CA, Weller IVD, Waite J, et al. Impaired responsivenessof homosexual men with HIV antibodies to plasma derivedhepatitis B vaccine. BMJ 1987;294:866-8.

3 Collier AC, Corey L, Murphy VL, Handsfield HH. Antibody tohuman immunodeficiency virus (HIV) and suboptimal res-ponse to hepatitis B vaccination. Ann Intern Med 1988;109:101-5.

4 Dowsett JS, Miller RF, Davidson R, et al. Sclerosing cholangitisin acquired immunodeficiency syndrome. Scan J Gastroenterol1988;23: 1267-74.

5 McGowan I, Weller IVD. AIDS and the Gut. In: Pounder RE,ed. Recent Advances in Gastroenterology. Edinburgh: Chur-chill Livingstone, 1990;8:133-56.

6 Raviglione MC, Battan R, Pablos-Mendez A, Aceves-Caillas P,Muller MP, Tarante A. Infections associated with Hickmancatheters in patients with acquired immunodeficiency syn-drome. Am J Med 1989;86:780-6.

7 Jacobson MA, Gellermann H, Chambers H. Staphylococcusaureus bacteraemia and recurrent staphylococcal infection inpatients with acquired immunodeficiency syndrome andAIDS-related complex. Am J Med 1988;85:172-6.

8 Guarda LA, Luna MA, Smith JL, Mansell PWA, Gyorkey F,Roca AN. Acquired immune deficiency syndrome: postmor-tem findings. Am J Clin Pathol 1984;81:549-57.

9 Neidt GW, Schinella RA. Acquired immunodeficiency syn-dromes. Clinicopathological study of 56 autopsies. ArchPathol Lab Med 1985;109:727-34.

Accepted for publication 22 January 1991

161

on Novem

ber 18, 2020 by guest. Protected by copyright.

http://sti.bmj.com

/G

enitourin Med: first published as 10.1136/sti.67.2.156 on 1 A

pril 1991. Dow

nloaded from