Bronchoscopy in the Diagnosis and Treatment of Bronchiectasis
Clinico-pathological Conference · sarcoma at bronchoscopy may have made this patient more...
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Genitourin Med 1994;70:51-55 Clinico-pathological Conference Recurrent pseudomembranous colitis due to Clostrzdium difficile in AIDS D R Churchill, S B Lucas, I Williams, N M Foley, R F Miller Department of Medicine, Middlesex Hospital, London, W1N 8AA D R Churchill Department of Histopathology S B Lucas Academic Department of Genitourinary Medicine I Williams Department of Medicine, University College London Medical School, London, W1N 8AA R F Miller Department of Thoracic Medicine, Royal Free Hospital, London NW3 2QG N M Foley Address correspondence to: Dr R F Miller, Departnent of Medicine, UCLMS, First Floor Crosspiece, Middlesex Hospital, London, WIN 8AA, UK Accepted for publication 28 September 1993 Figure 1 Plain abdominal radiograph showing marked gaseous distension of the transverse colon. Case report (Dr D R Churchill) A 34 year old homosexual Afro-Caribbean man was admitted with a one week history of profuse watery diarrhoea, passing liquid stools every 15-20 minutes, and diffuse abdominal pain. Eleven days previously he had completed a 7 day course of oral flu- cloxacillin (500 mg four times daily) and intravenous cefuroxime (750 mg three times daily) as treatment for cellulitis of his forearm and a bacterial chest infection. The patient had been born in the West Indies but had lived in England since he was two years old. Four years before this ad- mission he was found to be HIV-1 antibody positive and two years later he had bronchoscopically confirmed Pneumocystis carinii pneumonia, at which time cutaneous and palatal Kaposi's sarcoma was noted. He had a second episode of pneumocystis pneu- monia four months before the onset of his current symptoms; following this episode he had begun secondary antipneumocystis pro- phylaxis with monthly inhaled pentamidine. Examination on admission showed him to be pyrexial, 38°C, clinically dehydrated, hypotensive (BP = 95/75 mmHg) lying down and oliguric. Investigations showed serum creatinine was 242 (normal = 50-125) umol/l, blood urea = 21.7 (normal = 3-0-8.0) mmol/l. The total white blood cell count was 1.8 x 109/1 (neutrophils 0.8 x 109/1) and the CD4 count was 0.01 (normal = 0.35-2 2) x 109/1 being 1% of the total lymphocyte count. He was given intravenous rehydration and his clinical condition and renal function tests improved. However his diarrhoea per- sisted. Stool culture was negative for Shigella, Salmonella and Campylobacter species, and acid and alcohol fast bacilli (AAFB) were not seen. Two days after admission he developed abdominal distension and rebound tender- ness. An abdominal radiograph showed marked gaseous distension of the transverse colon (fig 1). Sigmoidoscopy revealed liquid bloody stool and a mild proctitis. The follow- ing day Clostridium difficile toxin was found in the stools. Oral vancomycin (125 mg four times daily) was given for seven days; his diarrhoea and abdominal pain rapidly improved. The day after completing vanco- mycin he again became unwell with fever, dyspnoea and a non-productive cough. Arterial blood gases revealed hypoxia, PaO2 = 8.0kPa, breathing air, and a chest radiograph showed consolidation in the left mid zone; blood cultures were negative. It was felt he had a bacterial pneumonia and he was treated initially with oral erythromycin and when he failed to respond to this, treatment was changed to intravenous cefuroxime (750 mg three times daily), flucloxacillin (400 mg four times daily) and gentamicin (80 mg three times daily). The patient made a slow but steady recovery. Twenty three days after admission he suddenly became unwell with a high fever of 39 5°C. At this time he was neutropenic, 0.6 x 109/1. A repeat sample of stool was negative for C difficile toxin but Staphylococcus epidermidis was isolated from blood cultures. Intravenous teicoplanin (200 mg once daily) was given for 8 days and the patient rapidly recovered, only to develop left orchitis due to Pseudomonas aeruginosa. This was compli- cated by an epididymal abscess which required surgical drainage and a further course of gentamicin was given. After 7 weeks in hospital the patient was discharged to a hospice. He remained there for four weeks but was then readmitted with a two week history of constant lower abdominal pain and rectal bleeding without diarrhoea. 51 on August 21, 2021 by guest. Protected by copyright. http://sti.bmj.com/ Genitourin Med: first published as 10.1136/sti.70.1.51 on 1 February 1994. Downloaded from
Transcript of Clinico-pathological Conference · sarcoma at bronchoscopy may have made this patient more...
Genitourin Med 1994;70:51-55
Clinico-pathological Conference
Recurrent pseudomembranous colitis due toClostrzdium difficile in AIDS
D R Churchill, S B Lucas, I Williams, NM Foley, R F Miller
Department ofMedicine, MiddlesexHospital, London,W1N 8AAD R ChurchillDepartment ofHistopathologyS B LucasAcademicDepartment ofGenitourinaryMedicineI WilliamsDepartment ofMedicine, UniversityCollege LondonMedical School,London, W1N 8AAR F MillerDepartment ofThoracic Medicine,Royal Free Hospital,London NW3 2QGN M FoleyAddress correspondence to:Dr R F Miller, Departnentof Medicine, UCLMS, FirstFloor Crosspiece, MiddlesexHospital, London, WIN8AA, UKAccepted for publication28 September 1993
Figure 1 Plainabdominal radiographshowing marked gaseousdistension of the transversecolon.
Case report (DrD R Churchill)A 34 year old homosexual Afro-Caribbeanman was admitted with a one week history ofprofuse watery diarrhoea, passing liquidstools every 15-20 minutes, and diffuseabdominal pain. Eleven days previously hehad completed a 7 day course of oral flu-cloxacillin (500 mg four times daily) andintravenous cefuroxime (750 mg three timesdaily) as treatment for cellulitis of his forearmand a bacterial chest infection.The patient had been born in the West
Indies but had lived in England since he wastwo years old. Four years before this ad-mission he was found to be HIV-1 antibodypositive and two years later he hadbronchoscopically confirmed Pneumocystiscarinii pneumonia, at which time cutaneousand palatal Kaposi's sarcoma was noted. Hehad a second episode of pneumocystis pneu-monia four months before the onset of hiscurrent symptoms; following this episode hehad begun secondary antipneumocystis pro-phylaxis with monthly inhaled pentamidine.
Examination on admission showed him tobe pyrexial, 38°C, clinically dehydrated,hypotensive (BP = 95/75 mmHg) lying downand oliguric. Investigations showed serum
creatinine was 242 (normal = 50-125)umol/l, blood urea = 21.7 (normal = 3-0-8.0)mmol/l. The total white blood cell count was1.8 x 109/1 (neutrophils 0.8 x 109/1) and theCD4 count was 0.01 (normal = 0.35-2 2)x 109/1 being 1% of the total lymphocytecount. He was given intravenous rehydrationand his clinical condition and renal functiontests improved. However his diarrhoea per-sisted. Stool culture was negative for Shigella,Salmonella and Campylobacter species, andacid and alcohol fast bacilli (AAFB) were notseen. Two days after admission he developedabdominal distension and rebound tender-ness. An abdominal radiograph showedmarked gaseous distension of the transversecolon (fig 1). Sigmoidoscopy revealed liquidbloody stool and a mild proctitis. The follow-ing day Clostridium difficile toxin was found inthe stools. Oral vancomycin (125 mg fourtimes daily) was given for seven days; hisdiarrhoea and abdominal pain rapidlyimproved. The day after completing vanco-mycin he again became unwell with fever,dyspnoea and a non-productive cough.Arterial blood gases revealed hypoxia, PaO2 =8.0kPa, breathing air, and a chest radiographshowed consolidation in the left mid zone;blood cultures were negative. It was felt hehad a bacterial pneumonia and he was treatedinitially with oral erythromycin and when hefailed to respond to this, treatment waschanged to intravenous cefuroxime (750 mgthree times daily), flucloxacillin (400 mg fourtimes daily) and gentamicin (80 mg threetimes daily). The patient made a slow butsteady recovery.Twenty three days after admission he
suddenly became unwell with a high fever of39 5°C. At this time he was neutropenic,0.6 x 109/1. A repeat sample of stool wasnegative for C difficile toxin but Staphylococcusepidermidis was isolated from blood cultures.Intravenous teicoplanin (200 mg once daily)was given for 8 days and the patient rapidlyrecovered, only to develop left orchitis due toPseudomonas aeruginosa. This was compli-cated by an epididymal abscess whichrequired surgical drainage and a furthercourse of gentamicin was given.
After 7 weeks in hospital the patient wasdischarged to a hospice. He remained therefor four weeks but was then readmitted with atwo week history of constant lower abdominalpain and rectal bleeding without diarrhoea.
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Figure 2 Plain abdominalradiograph showingextensive "thumb printing"of colonic mucosa, inaddition to gaseousdistension.
An abdominal radiograph (fig 2) showedgaseous distension of the colon with extensive"thumb printing" of the colonic mucosa.
Sigmoidoscopy revealed florid pseudomem-branous colitis. Rectal biopsy confirmed a
proctitis: no crypt abscesses were seen andspecial stains did not detect cryptosporidia or
cytomegalovirus. A stool sample was positivefor C difficile toxin. A further course of oralvancomycin was prescribed with rapidimprovement in symptoms. Subsequent stoolsamples on day 16 and day 21 were negativefor C difficile toxin. Two weeks later diarrhoearecurred and C difficile toxin was identified inthe stool; oral metronidazole (400 mg threetimes daily) was given with resolution ofsymptoms and the stool was again negativefor C difficile toxin.
This time the patient reported visual dis-turbance in both eyes, cytomegalovirus retini-
Figure 3 Chest radiographshowing Hickman line andbilateral diffuse shadowing.
tis was diagnosed on the basis of typical reti-nal appearances. Ganciclovir was commenced(5 mg/kg intravenously twice daily) and aHickman line was inserted. After three weekstreatment there had been stabilisation invisual symptoms and an improvement inretinal appearances and so ganciclovir wasreduced to maintenance dose (5 mg/kg intra-venously daily). A chest radiograph takenafter placement of the Hickman line (fig 3)showed diffuse shadowing. In the lower zonesthe shadowing was patchy but more confluentin the upper zones. Fibreoptic bronchoscopywas performed and showed extensive endo-bronchial Kaposi's sarcoma. Bronchoalveolarlavage from the right lower lobe was negativefor P carinii and other pathogens.
It was planned to give chemotherapy astreatment for the pulmonary Kaposi's sar-coma but the patient's condition suddenlydeteriorated with onset of diffuse abdominalpain and profuse diarrhoea. Stool cultureswere again positive for C difficile toxin.Terminally the patient became hypotensiveand clinically septicaemic; despite resuscita-tive measures he died eleven weeks afteradmission.
Discussion (Dr. I Williams)This 34 year old man had advanced HIVdisease with profound immunosuppression.His CD4 count was 0.01 x 109/1 and he hadpneumocystis pneumonia two years previ-ously. He then presented with severe diar-rhoea, abdominal pain, salt and waterdepletion and fever. There are several possi-ble causes for acute diarrhoea in thispopulation of patients.' (table 1) Firstly,cryptosporidiosis may present with profusewatery diarrhoea and abdominal pain.23 Inadvanced HIV disease it is difficult to treatand is associated with a poor prognosis. Inthis patient examination of multiple stoolspecimens and rectal biopsy did notdemonstrate cryptosporidium. Secondly,cytomegalovirus (CMV) disease is commonin patients with CD4 counts less than 0O05 x109/1.4 This patient was noted to have CMVretinitis later on the course of his illness.Severe CMV colitis5 can occur but the rectalbiopsy did not show typical features, andtreatment with ganciclovir did not influence
Table 1 Causes ofdiarrhoea in HIV-infected patients
(A) Infections(i) bacteria Salmonela species
Shigella.speciesClostridium difficieCampylobacterjejuni
(ii) mycobacteria Mycobacterium avium-intracelulare(iii) viruses cytomegalovirus
Herpes simplex virusadenovirus
(iv) protozoa CryptosporidiumMicrosporidiaIsospora belli
(B) Other causes(i) HIV enteropathy(ii) extensive Kaposi's sarcOma(iii) lymphoma of small bowel(iv) chronic pancreatitis
(a) secondary to HIV infection(b) secondary to therapy
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Recurrent pseudomembranous colitis due to Clostridium difficile in AIDS
the diarrhoeal illness; however, it remains apossibility in this patient. The abdominal ten-derness and marked distension of the trans-verse colon seen on the abdominal radiographsuggest a toxic megacolon. Bacterial entericinfections are known to cause severe colitis inpatients with HIV disease particularly Shigellaand Salmonella species.26 Repeated stool cul-tures for bacteria were negative in this man.Of other non-infectious causes of diarrhoea,Kaposi's sarcoma in the gut can cause symp-toms if extensive but lesions are often clini-cally silent.2 7 This patient had bothcutaneous and palatal Kaposi's sarcoma diag-nosed two years previously but it is unlikelythat bowel involvement was contributing tohis illness. The incidence of non-Hodgkin'slymphoma is increased in patients withadvanced HIV disease and in the bowel maypresent with multiple symptoms, dependingon the site, including abdominal pain anddiarrhoea.The clinical presentation in this man sug-
gests an acute gastrointestinal infection andthe subsequent finding of Clostridium difficiletoxin in stool cultures and the presence ofpseudomembranes on sigmoidoscopy con-firmed this. In case series of infectious causesof diarrhoea in patients with AIDS,Clostridium difficile has been reported, but itappears to be an uncommon pathogen.89 Inview of the marked immunosuppression, highrate of hospitalisation and frequent use ofantibiotics in patients with AIDS this seems
surprising and may represent under diagno-sis. Numerous antibiotics have been impli-cated in causing pseudomembranous colitis.This patient received treatment for a cellulitisprior to his admission with diarrhoea, sub-sequently he was given several courses ofantibiotics for a bacterial pneumonia andan epididymal abscess. Antibiotic-associateddiarrhoea may occur in the absence ofClostridium difficile but when Clostridium diffi-cile is present it is associated withpseudomembranous colitis and may causesevere abdominal pain, fever, bloody diar-rhoea, toxic megacolon and secondary bowelperforation.8 Despite treatment with bothvancomycin and metronidazole, this patient'srecurrent episodes of Clostridium difficileinfection were probably secondary to persis-tent carriage of the organism in the gut,rather than due to re-infection. Use of alter-native treatment, such as cholestyramine,would not have altered the outcome. Multiplefactors such as an underlying HIV enteropa-thy, the presence of CMV, recurrent bacterialinfections and the profound immuno-sup-pression may have all contributed to thispatient's diarrhoeal disease and outcome.The finding of endobronchial Kaposi's
sarcoma at bronchoscopy may have madethis patient more susceptible to bacterialpneumonia, alternatively bronchiectasis may
occur following severe episodes of pneumo-cystis pneumonia and may have contributedto this man's respiratory illness. The findingof confluent shadowing in the upper zones ofboth lungs on the chest radiograph suggested
a clinical diagnosis of pneumocystis pneumo-nia particularly as he had been receivinginhaled pentamidine as secondary prophy-laxis. Some patients receiving this form ofprophylaxis may relapse and present withupper lobe pneumocystis pneumonia.
Discussion (Dr Noeleen Foley)This patient's history illustrates one of themost common clinical problems in AIDS,namely diarrhoea, and one of its leastfrequent causes: Clostridium difficile. DrWilliams has discussed the differential diag-nosis of diarrhoea in patients with advanceddisease-and I agree that CMV infection wouldbe high on the list, as either a co-pathogen orsole agent, particularly during the secondepisode described, when there was little diar-rhoea but rectal bleeding occurred and theplain abdominal radiograph showed thumb-printing.
Diarrhoea is one of the most frequentsymptoms in patients with AIDS, occurringin up to 90% of patients.10 There is also someevidence that patients with AIDS who havediarrhoea have a greater degree of immunesuppression than those who do not have thissymptom. In the majority of patients, aninfectious pathogen can be identified in thestool (up to 80%) and diarrhoea may bepolymicrobial. 2 710 The organisms responsi-ble vary depending on the geographical areain which the patient lives and the stage ofdisease. Among the commonest pathogens inEuropean and North American patients arebacteria such as Salmonella, Shigella andCampylobacter, mycobacteria such as M aviumintracellulare, parasites such as Entamoebahistolytica and viruses such as adenovirus andcytomegalovirus.
In a review of diarrhoea in patients withAIDS a three stage protocol for investigationhas been suggested.2 (table 2) In practicemost units would carry out the investigationsdescribed in step 1 in all patients, althoughexamination for C difficile toxin is not routine
Table 2 Investigation ofdiarrhoea in patients withAIDS
Step 1(a) Culture stool for Salmonella species, ShigeUa flexneri and
Campylobacterjejuni (minimum 3 samples).(b) Assay for Clostridium difficie toxin.(c) Stain and culture stool for alcohol and acid fast bacilli
(AAFB) and fungi.(d) Examine stool for parasites.
Step 2(a) Sigmoidoscopy and rectal biopsy.(b) Endoscopy (colonoscopy and oesophagogastroduo-
denoscopy) in order to examine bowel and obtain biopsyspecimens and luminal material.
(c) Colonic biopsy specimens cultured for CMV, adenovirus,mycobacteria and Herpes simplex virus.
(d) Duodenal biopsy specimens cultured for CMV and myco-bacteria.
(e) Staining of biopsy specimens for protozoa, viral inclusionsand AAFB.
(f) Staining of duodenal fluid for protozoa.
Step 3Electron microscopy examination of biopsy specimens forMicrosporidia (duodenal biopsy) and adenovirus (colonicbiopsy).
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Figure 4 Liver showingdark red lesions ofKaposi'ssarcoma extendingfromthe portal tracts.
in many centres. Sigmoidoscopy and biopsyare commonly performed but the results ofthese investigations are usually awaited beforeproceeding to colonoscopy or upper gastro-intestinal endoscopy.
It is important to note that there is a highyield of specific pathogens in patients withAIDS, that infection with enteric pathogensrarely resolves spontaneously and that specific
Figure S Transverse colonshowing multiple smallplaques ofexudate, typicalofpseudomembranouscolitis (unstained).
Figure 6 Colon histology:showing typical lesions ofpseudomembranous colitiswith a plaque ofexudateover dilated degeneratecrypts (haematoxylinand eosin, magnificationx 20).
therapy brings about improvement in up to75% of cases. In this case, specific therapyappears to have been effective, but the symp-toms relapsed more frequently than is usualwith C difficile. Organisms of C difficile maypersist after treatment which has effectivelyeliminated the toxin and there is a recurrencerate of up to 20%.Clinical diagnoses: 1. Pseudomembranous col-
itis due to ClostridiumdiJffcile.
2. Cutaneous, palatal andendobronchial Kaposi'ssarcoma.
3. Recurrent, apical pneu-mocystis pneumonia?
Pathology (Dr S B Lucas)The body was that of a thin black man. Onthe trunk and limbs were many lesions ofKaposi's sarcoma. The main pathologicalabnormalities were found in the respiratoryand alimentary tracts.
In the lungs there were Kaposi's sarcomain the trachea and in the lower lobe bronchiand lower zone parenchyma. Also Kaposi'swas present in the hilar lymph nodes. In theupper zones there was extensive Pneumocystiscarinii pneumonia with calcification-reflect-ing chronicity. Small lesions of Kaposi's werealso found on the palate, on the oesophagus,jejunum and in the caecum. Lesions werealso found in the liver radiating out from theportal tracts. (fig 4)
In the large bowel there was severepseudomembranous colitis extending fromthe caecum to rectum (figs 5 & 6) but therewas no histological evidence of CMV. In theleft testis there was scarring, and Gram-nega-tive rods seen in vessel walls were indicativeof Pseudomonas infection.The brain had only very scanty non-spe-
cific microglial nodules. Multiple sections ofthe right eye failed to reveal CMV infection.
Pathological diagnoses: 1. Pseudomembranouscolitis.
2. Pneumocystis cariniipneumonia of upperlobes.
3. Kaposi's sarcoma ofskin, lungs, bowel.
4. Residual Gram-neg-ative rod infection.
Discussion (Dr R F Miller)Since this case we have seen two otherHIV positive patients with Clostridium difficilediarrhoea. The first was a 45 year old hetero-sexual Caucasian man who became neutro-penic secondary to chemotherapy given fortreatment of disseminated non-Hodgkin'slymphoma. He had received intravenousceftazidime as empirical treatment for neutro-penic fever and then developed diarrhoea.Clostridium difficile was identified in the stool;his symptoms resolved with oral vancomycintherapy. The second patient, a 42 year oldhomosexual Caucasian man, developedClostridium difficile diarrhoea whilst receiving
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rifampicin, ethambutol and clarithromycin as
treatment for disseminated Mycobacteriumavium-intracellulare infection and co-trimoxa-zole as secondary prophylaxis against pneu-mocystis pneumonia.
We thank Jane Healing for typing the manuscript.
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