PYREXIA OF PYREXIA OF UNKNOWN ORIGINUNKNOWN ORIGIN

Dr Henry SunpathDr Henry Sunpath

Head of MedicineHead of Medicine

Mc Cord HospitalMc Cord Hospital

3 September 20093 September 2009

Outline of presentationOutline of presentation

APPROACH TO PUOAPPROACH TO PUO PUO AND HIVPUO AND HIV LOOKING FOR OTHER CAUSES=NTSLOOKING FOR OTHER CAUSES=NTS POST ART =FEVERPOST ART =FEVER PRE ARTRE= AND FEVERPRE ARTRE= AND FEVER

MR B.S 28 years oldMR B.S 28 years old

Admitted 7/10/07 with Fever and Nt sweats > Admitted 7/10/07 with Fever and Nt sweats > 3/52 found to have pericardial effusion on US 3/52 found to have pericardial effusion on US scan and started emperically on TB tx also T/F scan and started emperically on TB tx also T/F 2 units of blood for normocytic anaemia Hb 5.6 2 units of blood for normocytic anaemia Hb 5.6

Recent HIV test apparantly negative but result Recent HIV test apparantly negative but result not seen by our teamnot seen by our team

Given FU app for to assess response to txGiven FU app for to assess response to tx

Readmitted 16/10Readmitted 16/10

PC persisting fevers and nt sweats with PC persisting fevers and nt sweats with continued wt losscontinued wt loss

OE Pale, pyrexic small mobile LN lt posterior OE Pale, pyrexic small mobile LN lt posterior cervical areacervical area

No rash, joints NAD, RS,ABDO NADNo rash, joints NAD, RS,ABDO NAD Soft PSM dynamic cardiac pulsation Soft PSM dynamic cardiac pulsation Pulse 104 BP 115/65 Pulse 104 BP 115/65 Neurological OE Normal Neurological OE Normal

InvestigationsInvestigations

FBC: Hb 7.38 Mcv 78 ESR 142FBC: Hb 7.38 Mcv 78 ESR 142 Wcc 18.6 Neut 15.7 Lym 2.19Wcc 18.6 Neut 15.7 Lym 2.19 Plats 557Plats 557 Film : Hypochromic,microcyticFilm : Hypochromic,microcytic UE: 131,3.6,102,26,3.6,74UE: 131,3.6,102,26,3.6,74 LFT: NAD Alb 18LFT: NAD Alb 18 CXR: Normal Urinalysis NADCXR: Normal Urinalysis NAD

Working diagnosisWorking diagnosis

1: Bacterial endocardtis1: Bacterial endocardtis 2: TB with slow response to tx2: TB with slow response to tx

PLAN started on high dose penicillin and PLAN started on high dose penicillin and gentamicin awaiting blood cultures gentamicin awaiting blood cultures

TB tx continued TB tx continued Sent for echo and US at Parklands Sent for echo and US at Parklands

ABDO US : Mild Splenomegaly otherwise ABDO US : Mild Splenomegaly otherwise NAD with no nodes seen NAD with no nodes seen

ECHO : slightly dilated LV Good LV ECHO : slightly dilated LV Good LV function , small pericardial effusion 0.8 mmfunction , small pericardial effusion 0.8 mm

No vegetations or valve lesions seenNo vegetations or valve lesions seen

Blood culture Negative Blood culture Negative

Continued investigatonsContinued investigatons

Bone marrow: hypocellular marrow with no Bone marrow: hypocellular marrow with no evidence of infiltration ,constistent with evidence of infiltration ,constistent with combined nutrional deficiency and combined nutrional deficiency and systemic illnesssystemic illness

Malaria and widal negativeMalaria and widal negative WR negativeWR negative C3 + C4 Normal awaiting ANF C3 + C4 Normal awaiting ANF Lymph node histology =Follicular Lymph node histology =Follicular

hyperplasia non specific finding hyperplasia non specific finding

ProgressProgress

Completed 10/7 of iv AB and continued Completed 10/7 of iv AB and continued TB treament but spiking fever persistedTB treament but spiking fever persisted

Patient becoming increasingly despondant Patient becoming increasingly despondant on ward and allowed to go home with FU on ward and allowed to go home with FU

Declined further HIV test while on ward Declined further HIV test while on ward despite counsellingdespite counselling

Problem listProblem list

P.U.OP.U.O Pericardial effusionPericardial effusion Mild LV dilatationMild LV dilatation Mild splenomegalyMild splenomegaly Anaemia [microcytic]+hypocellular marrowAnaemia [microcytic]+hypocellular marrow Neutrophil leucocytosisNeutrophil leucocytosis Hypoalbuminaemia Hypoalbuminaemia

Possible DiagnosesPossible Diagnoses

Infective: Pulmonary/ Extrapulmonary TBInfective: Pulmonary/ Extrapulmonary TB Mycobacterium avium [MAI]Mycobacterium avium [MAI] MDR TB MDR TB Disseminated fungalDisseminated fungal CMV CMV Malignancy: LymphomaMalignancy: Lymphoma Collagen vascular diseasesCollagen vascular diseases Granulamatous : sarcoidGranulamatous : sarcoid

Future plans on review Future plans on review

? CT SCAN of Chest and Abdomen looking for ? CT SCAN of Chest and Abdomen looking for lymphoma or hidden abscess collectionlymphoma or hidden abscess collection

? Try pericardial tap for culture and cytology? Try pericardial tap for culture and cytology ? Further biopsy ie Liver ? Further biopsy ie Liver Repeated Blood cultures specifically looking for Repeated Blood cultures specifically looking for

TB,Fungal inf etcTB,Fungal inf etc Serological tests for CMVSerological tests for CMV Any other ideas? [need to confirm HIV status] Any other ideas? [need to confirm HIV status]

Fever of unknown origin Fever of unknown origin

Classic PUO 3/52 Fever + 1 week of Classic PUO 3/52 Fever + 1 week of investigationinvestigation

Nosocomial 3/7 OF IXNosocomial 3/7 OF IX Neutropenic 3/7 OF IXNeutropenic 3/7 OF IX HIV asociated 4/52 OPD 3/7 inpatientHIV asociated 4/52 OPD 3/7 inpatient

CAUSES CLASSIC PUOCAUSES CLASSIC PUO

INFECTIVE 20-30%INFECTIVE 20-30% CANCER 10-20%CANCER 10-20% AUTOIMMUNE 15-20%AUTOIMMUNE 15-20% MISC 15-25%MISC 15-25% UNDIAGNOSED 5-10%UNDIAGNOSED 5-10%

INFECTIVEINFECTIVE

Localised pyogenic infectionLocalised pyogenic infection Systemic bacterial eg typhoidSystemic bacterial eg typhoid Mycobacterial MTB,MAIMycobacterial MTB,MAI Fungal eg cryptococcusFungal eg cryptococcus Viral eg HIV,CMVViral eg HIV,CMV Parastitic eg Malaria,ToxoplasmosisParastitic eg Malaria,Toxoplasmosis Rickettsial eg Q feverRickettsial eg Q fever

CANCERSCANCERS

LYMPHOMALYMPHOMA LEUKAEMIALEUKAEMIA LIVER,RENAL,COLON,PANCREATICLIVER,RENAL,COLON,PANCREATIC SARCOMASARCOMA ATRIAL MYXOMASATRIAL MYXOMAS

Collagen vascular diseasesCollagen vascular diseases

SLESLE RARA PANPAN WEGENERSWEGENERS STILLSSTILLS Polymyalgia rheumaticaPolymyalgia rheumatica Rheumatic feverRheumatic fever BehcetsBehcets

MISCMISC

GRANULOMATOUS ie Sarcoid ,CrohnsGRANULOMATOUS ie Sarcoid ,Crohns DRUG induced feverDRUG induced fever ENDOCRINE ie ENDOCRINE ie

thyrotoxicosis,phaeocrocytomathyrotoxicosis,phaeocrocytoma INTRACERBRAL ie SOL,pontine INTRACERBRAL ie SOL,pontine

CVA,encephalitisCVA,encephalitis METABOLIC /INHERITED ie familial METABOLIC /INHERITED ie familial

mediteranian fevermediteranian fever Tissue infarction ie Post MI, Rec PE Tissue infarction ie Post MI, Rec PE

HIV associated PUOHIV associated PUO

HIV aloneHIV alone TB,M avium/intracelulareTB,M avium/intracelulare ToxoplasmosisToxoplasmosis CMV ,PCP ,SalmonellaCMV ,PCP ,Salmonella Cryptococcus,HistoplasmosisCryptococcus,Histoplasmosis Non Hodgkins LymphomaNon Hodgkins Lymphoma Drug inducedDrug induced

OTHER CAUSES ASSOCIATED WITH OTHER CAUSES ASSOCIATED WITH FEVER=TTP/HUSFEVER=TTP/HUS

Non Typhoid salmonella…the need to Non Typhoid salmonella…the need to screen in SAVER=TTP/HUS,screen in SAVER=TTP/HUS,

Look for candidemia as a cause of PUO Look for candidemia as a cause of PUO in ICU pts-in ICU pts-

NomenclatureNomenclature

DNA hybridization studies show that DNA hybridization studies show that medically important Salmonellae medically important Salmonellae organisms can be considered as a single organisms can be considered as a single species known as species known as Salmonellae entericaSalmonellae enterica

S. typhiS. paratyphi

>2000 remaining Nontyphoid serotypes•Grouped as NTS

Background- Salmonellae Background- Salmonellae infection in HIV infected African infection in HIV infected African

adultsadults Pattern of HIV related disease seen in Africa is known to Pattern of HIV related disease seen in Africa is known to

be different from that seen in the developed world. be different from that seen in the developed world. (Grant (Grant AD, Djomand G, de Cock KM. Natural history and spectrum of disease in adults with HIV/AIDS in AD, Djomand G, de Cock KM. Natural history and spectrum of disease in adults with HIV/AIDS in Africa. AIDS 1997;11(suppl B):S43-S54)Africa. AIDS 1997;11(suppl B):S43-S54)

Bacterial infections and TB predominateBacterial infections and TB predominate NTS septicaemia is one of the most frequent NTS septicaemia is one of the most frequent

manifestations of HIV in adults in Africa.manifestations of HIV in adults in Africa. Most case series have found that focal metastatic NTS Most case series have found that focal metastatic NTS

infections in HIV are rareinfections in HIV are rare Case reports of focal infection in literature Case reports of focal infection in literature

Pulmonary involvement in HIV patients with NTS Pulmonary involvement in HIV patients with NTS bacteraemia is well recognisedbacteraemia is well recognised May represent isolated NTS lung disease or co-infection May represent isolated NTS lung disease or co-infection

with second respiratory pathogenwith second respiratory pathogen

Pattern of Bacteremia in HIV Pattern of Bacteremia in HIV Positive African adultsPositive African adults

NTS as a common cause of bacteraemia illness in HIV-NTS as a common cause of bacteraemia illness in HIV-positive patients is now an established pattern in HIV positive patients is now an established pattern in HIV endemic areas of Africa. endemic areas of Africa. (Grant AD, Djomand G, de Cock KM. Natural history (Grant AD, Djomand G, de Cock KM. Natural history and spectrum of disease in adults with HIV/AIDS in Africa. AIDS 1997;11(suppl B):S43-S54)and spectrum of disease in adults with HIV/AIDS in Africa. AIDS 1997;11(suppl B):S43-S54)

This pattern is distinct from that seen in HIV-positive This pattern is distinct from that seen in HIV-positive patients in Europe or North America.patients in Europe or North America. Greater proportion of total isolates are Gram-postive, and Greater proportion of total isolates are Gram-postive, and

S. aureus is the most common organism S. aureus is the most common organism • Related to either IV drug use or intravenous access Related to either IV drug use or intravenous access

devicesdevices Gram-negative isolates from smaller proportion of totalGram-negative isolates from smaller proportion of total

• NTS are commonest group of organismsNTS are commonest group of organisms

Clinical Course of NTS Clinical Course of NTS bacteraemia in HIV-Positive bacteraemia in HIV-Positive

African AdultsAfrican Adults Non-typhoidal salmonella bacteraemia Non-typhoidal salmonella bacteraemia

among HIV-infected Malawian adults: high among HIV-infected Malawian adults: high mortality and frequent recrudescence. mortality and frequent recrudescence. AIDSAIDS 2002 2002.. Prospective study that enrolled 100 Prospective study that enrolled 100

consecutive adult inpatients with NTS consecutive adult inpatients with NTS bacteraemiabacteraemia

Patients Treated with chloramphenicol and Patients Treated with chloramphenicol and survivors followed to detect recurrence.survivors followed to detect recurrence.

Microbiological findingsMicrobiological findings

NTS blood isolates from 100 casesNTS blood isolates from 100 cases 75 – S. typhimurium75 – S. typhimurium 19 – S. enteritidis19 – S. enteritidis 1 – S. typhimurium + S. enteritidis1 – S. typhimurium + S. enteritidis 5 – other Salmonella spp.5 – other Salmonella spp.

Host Susceptibility for Host Susceptibility for SalmonellosisSalmonellosis

Extremes of ageExtremes of age Alteration of bowel endogenous bowel floraAlteration of bowel endogenous bowel flora DiabetesDiabetes MalignancyMalignancy Rheumatological disordersRheumatological disorders Reticuloendothelial blockageReticuloendothelial blockage

From Malaria or sickle cell diseaseFrom Malaria or sickle cell disease Therapeutic immunosuppression of all typesTherapeutic immunosuppression of all types HIV infectionHIV infection

Anatomic disruptionsAnatomic disruptions Kidney stones, urinary tract abnormalities, gallstones, Kidney stones, urinary tract abnormalities, gallstones,

atherosclerotic endovascular lesions, atherosclerotic endovascular lesions, schistosomiasisschistosomiasis, and , and prosthetic devices may serve as foci for persistent Salmonella prosthetic devices may serve as foci for persistent Salmonella infectioninfection

Focal NTS infection- Case Focal NTS infection- Case ReportsReports

Focal infections due to non-typhi Salmonella in patients Focal infections due to non-typhi Salmonella in patients with AIDS: report of 10 cases and review. Clin Infec Dis. with AIDS: report of 10 cases and review. Clin Infec Dis. 1997 Sep; 25(3):690-71997 Sep; 25(3):690-7 Ten of 38 HIV-infected patients (26.3%) with salmonellosis Ten of 38 HIV-infected patients (26.3%) with salmonellosis

documented over a period of 9 years had focal suppurative documented over a period of 9 years had focal suppurative complicationscomplications

Infections of the urinary tract, lungs, and soft tissue, Infections of the urinary tract, lungs, and soft tissue, followed by arthritis, endocarditis, and meningitis were followed by arthritis, endocarditis, and meningitis were most frequently seenmost frequently seen

Infectious endocarditis due to non-typhi Salmonella in Infectious endocarditis due to non-typhi Salmonella in patients infected with human immunodeficiency virus: patients infected with human immunodeficiency virus: report of two cases and review. Clin Infect Dis. 1996 report of two cases and review. Clin Infect Dis. 1996 May;22(5):853-5 May;22(5):853-5

Focal NTS infection- Case Focal NTS infection- Case ReportsReports

Salmonella pyomyositis in patients with the human Salmonella pyomyositis in patients with the human immunodeficiency virus. Br J Rheumatol. 1995 Jun; immunodeficiency virus. Br J Rheumatol. 1995 Jun; 34(6):568-7134(6):568-71

Salmonella septic arthritis in HIV patients. Br J Salmonella septic arthritis in HIV patients. Br J Rheumatol. 1993 Jan;32(1):88 Rheumatol. 1993 Jan;32(1):88

Nontyphoidal salmonella intracranial infections in Nontyphoidal salmonella intracranial infections in HIV-infected patients. Clin Infec Dis 1997, 25:1118-HIV-infected patients. Clin Infec Dis 1997, 25:1118-1120.1120.

Non-typhi Salmonella adrenal abscess in an HIV-Non-typhi Salmonella adrenal abscess in an HIV-infected patient. Case Reports.infected patient. Case Reports.

Liver abscess due to Salmonella enteritidis in a Liver abscess due to Salmonella enteritidis in a returned travelor with HIV infection: case report and returned travelor with HIV infection: case report and review of the literature. Rev. Inst. Med. Trop. S. review of the literature. Rev. Inst. Med. Trop. S. Paulo. March-April, 2003;45(2): 115-117Paulo. March-April, 2003;45(2): 115-117

Lung Involvement in HIV-positive Lung Involvement in HIV-positive PatientsPatients

Salmonella Lung Involvement in Patients Salmonella Lung Involvement in Patients with HIV Infection. with HIV Infection. CHESTCHEST1997.1997. Retrospective clinical study- studied records Retrospective clinical study- studied records

of all HIV-infected patients with Salmonella of all HIV-infected patients with Salmonella bacteraemia at a university tertiary hospital in bacteraemia at a university tertiary hospital in Spain from Jan 87 to Dec 95.Spain from Jan 87 to Dec 95.

FindingsFindings Lung involvement was frequentLung involvement was frequent

Present in 35% of HIV positive patients with NTS Present in 35% of HIV positive patients with NTS bacteraemiabacteraemia

33% of those with lung involvement had definite 33% of those with lung involvement had definite Salmonella pulmonary infectionSalmonella pulmonary infection

Predisposing factors for focal disease were not Predisposing factors for focal disease were not apparentapparent

Focal lung involvement with NTS was not associated Focal lung involvement with NTS was not associated with worse prognosiswith worse prognosis

56% of those with lung involvement had 56% of those with lung involvement had Superinfection with other respiratory pathogenSuperinfection with other respiratory pathogen 28% PCP28% PCP 17% pyogenic bacterial infections17% pyogenic bacterial infections 11% TB11% TB

Antimicrobial Susceptibility and Antimicrobial Susceptibility and ResistanceResistance

In developed countries there is great concern over development of antimicrobial In developed countries there is great concern over development of antimicrobial resistanceresistance

Increase in fluroquinolone resistance among Salmonellae serotypesIncrease in fluroquinolone resistance among Salmonellae serotypes Nairobi, KenyaNairobi, Kenya

48%-56% of isolates were resistant to 3 or more of the routinely available antimicrobials 48%-56% of isolates were resistant to 3 or more of the routinely available antimicrobials MalawiMalawi

5% resistant to chloramphenicol5% resistant to chloramphenicol 73% resistant to co-trimoxazole73% resistant to co-trimoxazole 79% resistant to ampicillin79% resistant to ampicillin 43% resistant to gentamycin43% resistant to gentamycin 40% resistant to tetracycline40% resistant to tetracycline

Bangui in Central Africa Bangui in Central Africa (Kassa-Kelembho et al. Bacteremia in adults admitted to the Department of Medicine on Bangui (Kassa-Kelembho et al. Bacteremia in adults admitted to the Department of Medicine on Bangui Community Hospital (Central Africa Republic). Acta Tropica. 2003;89:67-72)Community Hospital (Central Africa Republic). Acta Tropica. 2003;89:67-72)

12% resistant to chloramphenicol12% resistant to chloramphenicol 75% resistant to co-trimoxazole75% resistant to co-trimoxazole 80% resistant to amoxicillin80% resistant to amoxicillin 26% resistant to gentamycin26% resistant to gentamycin 56% resistant to tetracycline56% resistant to tetracycline 0% resistant to ceftriaxone0% resistant to ceftriaxone 0% resistant to ciprofloxacin0% resistant to ciprofloxacin

ConclusionsConclusions

Blood stream infections (BSI) with NTS Blood stream infections (BSI) with NTS are a major cause of morbidity and are a major cause of morbidity and mortality in African patients with HIV.mortality in African patients with HIV.

Treatment should be initiated empirically Treatment should be initiated empirically before final bacteriological results are before final bacteriological results are availableavailable

Knowledge about type of pathogens Knowledge about type of pathogens responsible for BSI and pattern of responsible for BSI and pattern of antibiotic resistance is keyantibiotic resistance is key

ConclusionsConclusions Consider NTS in Pt with Consider NTS in Pt with

HIV, CD4 <200, or clinical evidence of HIVHIV, CD4 <200, or clinical evidence of HIV and p/w fever and GI symptoms, or respiratory and p/w fever and GI symptoms, or respiratory

involvement or fever of unknown origininvolvement or fever of unknown origin Empirical treatment with chloramphenicol, Empirical treatment with chloramphenicol,

ceftriaxone, ciprofloxacin appears ceftriaxone, ciprofloxacin appears appropriateappropriate High resistance to penicillinsHigh resistance to penicillins

ARV treatment also prevents recurrenceARV treatment also prevents recurrence Sidovudine has been shown to protect against Sidovudine has been shown to protect against

Salmonellae bacterial recurrenceSalmonellae bacterial recurrence

IRIS AND FEVERIRIS AND FEVER

35 yo M with HIV infection35 yo M with HIV infection

HPI:HPI: June 2006: Diagnosed HIV (+) in the June 2006: Diagnosed HIV (+) in the setting of PCP. CD4 cell count: 9.setting of PCP. CD4 cell count: 9. July 28: Presented to begin ARVs. Pt July 28: Presented to begin ARVs. Pt complained of nausea and chronic complained of nausea and chronic diarrhea. Began D4T/3TC/EFV. Pt had diarrhea. Began D4T/3TC/EFV. Pt had an abnormal CXR thought to represent an abnormal CXR thought to represent resolving PCP infection.resolving PCP infection. Aug 10: Pt complained of nausea and Aug 10: Pt complained of nausea and vomiting and was treated with vomiting and was treated with metoclopromide. metoclopromide.

Aug 21: Admitted with worsening nausea, Aug 21: Admitted with worsening nausea, vomiting and diarrhea. He noted loss of weight vomiting and diarrhea. He noted loss of weight of 6 kg over 1 month. Unremarkable CXR of 6 kg over 1 month. Unremarkable CXR (results not available). No AFB + sputum. (results not available). No AFB + sputum. UUltrasound showedltrasound showed 'splenic granulomas' but 'splenic granulomas' but no abdominal lymphadenopathy. no abdominal lymphadenopathy. Pt was Pt was diagnosed with IRIS tuberculosis and he diagnosed with IRIS tuberculosis and he commenced standard combination anti-commenced standard combination anti-tuberculosis therapy. Pt reportedly responded tuberculosis therapy. Pt reportedly responded well clinically.well clinically.

Sept 12: Complained of persistent nausea and Sept 12: Complained of persistent nausea and vomiting at outpatient visit.vomiting at outpatient visit.

Oct 3: Admitted with delirium, fever & vomiting Oct 3: Admitted with delirium, fever & vomiting for 1 weekfor 1 week

Sodium 124 mmol/l; creatinine 80 mmol/l.Sodium 124 mmol/l; creatinine 80 mmol/l. Lumbar puncture: Lumbar puncture:

16 lymphocytes/mm3, neutrophils 2/mm3, red blood 16 lymphocytes/mm3, neutrophils 2/mm3, red blood cells 30/mm3. India Ink (+), gram stain (-). Protein 1.24 cells 30/mm3. India Ink (+), gram stain (-). Protein 1.24 g/l, glucose 1.5 mmol/l. Cryptococcal CSF antigen (+). g/l, glucose 1.5 mmol/l. Cryptococcal CSF antigen (+).

Diagnosed with IRIS cryptococcal meningitisDiagnosed with IRIS cryptococcal meningitis Treated with amphotericin, continued Treated with amphotericin, continued

antiretrovirals, cotrimoxazole and anti-tuberculosis antiretrovirals, cotrimoxazole and anti-tuberculosis therapy.therapy.

Became afebrile and mental status improved. Became afebrile and mental status improved. Discharged on to chronic care facility to complete Discharged on to chronic care facility to complete therapy. Received therapeutic lumbar punctures therapy. Received therapeutic lumbar punctures to manage intracranial pressure (never formally to manage intracranial pressure (never formally measured).measured).

Oct 20: Completed 14 days of amphotericin; changed Oct 20: Completed 14 days of amphotericin; changed to fluconazole 400 mg daily. to fluconazole 400 mg daily.

Oct 24: Switched to AZT/3TC/EFV due to severe Oct 24: Switched to AZT/3TC/EFV due to severe peripheral neuropathy. Pt remained at chronic care peripheral neuropathy. Pt remained at chronic care facility without fever but with "dull mental status," facility without fever but with "dull mental status," vomiting and hyponatremia. Thought to be clinically vomiting and hyponatremia. Thought to be clinically dehydrated and received intravenous fluids.dehydrated and received intravenous fluids.

Nov 2: Repeat CD4 5, VL unavailable.Nov 2: Repeat CD4 5, VL unavailable. Nov 6: Clinically he failed to improved and developed Nov 6: Clinically he failed to improved and developed

neutropenia w/ decreased hematocrit of 23% but neutropenia w/ decreased hematocrit of 23% but preserved platelets of 214 cells/ul. He died on Nov. 7 preserved platelets of 214 cells/ul. He died on Nov. 7 at chronic care facility.at chronic care facility.

Differential diagnosis of worsening Differential diagnosis of worsening of symptoms after HAART therapyof symptoms after HAART therapy

Patient with OITreated with ART

Asymptomatic immune recovery

Return of original symptoms

New Symptoms

Relapse IRIS New OIMedication Side-effects IRIS

Proposed Diagnostic Criteria for IRISProposed Diagnostic Criteria for IRIS(Adapted from: ACTG 2006(Adapted from: ACTG 2006, , Shelburne et al, 2002; French et Shelburne et al, 2002; French et

al 2005)al 2005)Required CriteriaRequired Criteria Worsening symptoms of Worsening symptoms of

inflammation/infection, inflammation/infection, disease progression or disease progression or enlargement of pre-existing enlargement of pre-existing lesions after definate clinical lesions after definate clinical improvement with anti-improvement with anti-microbial therapy pre-HAART microbial therapy pre-HAART

Temporal relationship with Temporal relationship with starting antiretroviral therapystarting antiretroviral therapy

Symptoms not explained by Symptoms not explained by newly acquired infection or newly acquired infection or disease, or the usual course disease, or the usual course of a previously acquired of a previously acquired diseasedisease

Decrease in HIV RNA level by Decrease in HIV RNA level by >>1 log1 log1010

Supportive CriteriaSupportive Criteria Increase in CD4+ count of Increase in CD4+ count of

>>25 cells/25 cells/ ｵｵ LL Atypical presentation of Atypical presentation of

“opportunistic infections or “opportunistic infections or tumours” tumours”

Biopsy demonstrating Biopsy demonstrating granulomatous granulomatous inflammation or unusually inflammation or unusually exuberant inflammatory exuberant inflammatory responseresponse

Spontaneous resolution Spontaneous resolution without specific without specific antimicrobial therapyantimicrobial therapy

MACMAC Focal Focal LymphadenitisLymphadenitisCMVCMV Vitreitis, Vitreitis, UveitisUveitisC. neoformansC. neoformans Marked Marked PleocytosisPleocytosisHepatitis CHepatitis C ↑HCV RNA & ↑HCV RNA & ALTALTHepatitis BHepatitis B ↑HBV DNA↑HBV DNA

Immune Restoration OI Immune Restoration OI Manifestations Are Often AtypicalManifestations Are Often Atypical

CASE 1: CASE 1: M. TB Immune M. TB Immune reconstitutionreconstitution

28 Black African female 24/40 gravid 28 Black African female 24/40 gravid diagnosed with pulmonary tuberculosis diagnosed with pulmonary tuberculosis and HIV positive in July 2002and HIV positive in July 2002 Living with sister and 6 year old sonLiving with sister and 6 year old son recently in Zambia 3/12 contact with brother recently in Zambia 3/12 contact with brother

who had just died of TBwho had just died of TB

PresentationPresentation• 3/52 - SOB, cough, fevers, weight loss3/52 - SOB, cough, fevers, weight loss• Febrile temp 40 Febrile temp 40 00C C • Cachectic; Left upper lobe crepitationsCachectic; Left upper lobe crepitations• Baseline CD4 cell count 59 (11%) and HIV Baseline CD4 cell count 59 (11%) and HIV

RNA viral load of 266,700 copies/mlRNA viral load of 266,700 copies/ml• Inadequate sputum sample; Bronchoscopy Inadequate sputum sample; Bronchoscopy

– BAL AFB negative (AFB culture positive)– BAL AFB negative (AFB culture positive)• CXR – dense L hilumCXR – dense L hilum

Infectious Infectious PathogensPathogens

M. tuberculosis M. tuberculosis M. avium complexM. avium complex CryptococcusCryptococcus Pneumocystis Pneumocystis CytomegalovirusCytomegalovirus Herpes simplexHerpes simplex HistoplasmosisHistoplasmosis Hepatitis B and CHepatitis B and C

•Herpes zoster•PML (JC virus)•Kaposi’s sarcoma

(HHV8)•M. leprae•Bartonella•Leishmania major•Chlamydia

trachomatis

Many Pathogens and Syndromes

Adapted from French et al, AIDS 2004

Auto-immune

•Grave’s disease

•SLE

•Sarcoidosis

•Guillain Barre

05

101520253035

%

TBMAC

M. xenopi

Crypto

coccusCMV

HBVHCV

Epidemiology of IRIS (CID 2000;30:882)

• Now >300 case series and reports in English literature

CD4 <200, start ARTMAC lymphadenitis

DX CMV retinitis start ARTCMV immune vitritis

1. “NEW” INFECTION

2. “EXISTING”INFECTION

Immune Reconstitution Syndrome: Clinical Settings

FEVER BEFORE STARTING FEVER BEFORE STARTING HAARTHAART

History -34 yr old women tested HIV History -34 yr old women tested HIV positive in Dec 2005.positive in Dec 2005.

Presented in Jan 2006 to GP with Presented in Jan 2006 to GP with oesophageal candidiasis and a history of oesophageal candidiasis and a history of cough with occasional loose stools since cough with occasional loose stools since Nov 2005.She also had 8 kg wt loss over Nov 2005.She also had 8 kg wt loss over tst 6 months..No other OI or HIV related tst 6 months..No other OI or HIV related illnessillness

EXAMINATION T-38.5 WITH SINUS EXAMINATION T-38.5 WITH SINUS TACHYCARDIA,WASTING,PALLOR AND TACHYCARDIA,WASTING,PALLOR AND SEVERE ORAL TRUSH. SEVERE ORAL TRUSH.

NO LN,LIVER OR SPLEENIC NO LN,LIVER OR SPLEENIC ENLARGEMENT.ENLARGEMENT.

RESPIRATORY EXAM =NORMALRESPIRATORY EXAM =NORMAL

INVESTIGATIONSINVESTIGATIONS

Hb -6.9 g/dl NNAHb -6.9 g/dl NNA WCC 5.6 AND PLT -88WCC 5.6 AND PLT -88 CD4-27 and VL=>750 000CD4-27 and VL=>750 000 S.Alb-22g/l S.Alb-22g/l LDH 3116 LDH 3116 LFT otherwise normalLFT otherwise normal Blood cultures –aerobic and anaerobic Blood cultures –aerobic and anaerobic

mycobacterial negativemycobacterial negative

Bone marrow trephine and aspirate-Bone marrow trephine and aspirate-disordered erytropoeisis in keeping with disordered erytropoeisis in keeping with HIV disease,Histology of the trephine-no HIV disease,Histology of the trephine-no granulomas or signs of malignancy.granulomas or signs of malignancy.

The CXR was normal.The CXR was normal.

Futhur courseFuthur course Treated with Diflucan and given blood transfusion.Treated with Diflucan and given blood transfusion. ART commenced Reg 1 a.ART commenced Reg 1 a. Symptomatic peripheral peripheral neuropathy Symptomatic peripheral peripheral neuropathy

after 2 weeks-change to AZT.after 2 weeks-change to AZT. Four weeks later clinical deterioration with Four weeks later clinical deterioration with

confusion and pallor but no fever.confusion and pallor but no fever. CXR=R pleural effusion-blood stainedCXR=R pleural effusion-blood stained CYTOLOGY=high grade plasma blastic NON CYTOLOGY=high grade plasma blastic NON

HODGKINS LYMPHOMAHODGKINS LYMPHOMA Refuse futhur treatment after assesment by an Refuse futhur treatment after assesment by an

oncologist and died.oncologist and died.

DISCUSSIONDISCUSSION Dillemma for clinicians of pt presenting with Dillemma for clinicians of pt presenting with

advanced HIV infection for the first time with advanced HIV infection for the first time with prominent constitutional symptoms.Careful prominent constitutional symptoms.Careful evaluation for Ois is unrevealing.Within weeks evaluation for Ois is unrevealing.Within weeks of nstarting ART a fatal disease process of nstarting ART a fatal disease process becomes apparentbecomes apparent

Advanced HIV infection can produce fever Advanced HIV infection can produce fever and wt loss /constitutional symptoms without and wt loss /constitutional symptoms without underlying OI.However this is a diagnosis of underlying OI.However this is a diagnosis of exclusionexclusion

These should be approached as PUOThese should be approached as PUO

Various forms of TB are the most common Various forms of TB are the most common causes of PUO.If cough is present then sputa causes of PUO.If cough is present then sputa should be sent for AFB stains.should be sent for AFB stains.

Other initial investigations should be Other initial investigations should be FBC,WITH DIF COUNTFBC,WITH DIF COUNT LFTLFT CRPCRP URINE ANALYSIS-WBC CASTS ?cultureURINE ANALYSIS-WBC CASTS ?culture CXRCXR

ULTRASOUND HEART/ABDOMEN to look ULTRASOUND HEART/ABDOMEN to look for effusions/fluid,lymph nodes,hepatic annd for effusions/fluid,lymph nodes,hepatic annd splenic lesions and pelvic masses.splenic lesions and pelvic masses.

TB IS SUGGESTED Bypulmonary TB IS SUGGESTED Bypulmonary infiltrates,fluid colections ,lymphnodes,splenic infiltrates,fluid colections ,lymphnodes,splenic lesions,lesions,

OTHER INFECTIONS AND MALIGNANCIES OTHER INFECTIONS AND MALIGNANCIES CAN ALSO PRESENT LIKE THIS!CAN ALSO PRESENT LIKE THIS!

MYCOBACTERIAL BLOOD CULTIRES MYCOBACTERIAL BLOOD CULTIRES may be used to using the BACTEC/Myco may be used to using the BACTEC/Myco /F lytic bottle TO DETECT /F lytic bottle TO DETECT BACTERIA,FUNGI ,NORCADIA as well BACTERIA,FUNGI ,NORCADIA as well as MTB and MAC and ?MOTTas MTB and MAC and ?MOTT

CSF studies –CRAG /India inkCSF studies –CRAG /India ink BMAT-if bicytopenia or pancytopenia BMAT-if bicytopenia or pancytopenia

presentpresent Liver biopsy if ALP and GGT raised.Liver biopsy if ALP and GGT raised. LN-FNAC or biopsy (normal saline and LN-FNAC or biopsy (normal saline and

formalin)formalin)

EMPERICAL TB TREATMENT WITH EMPERICAL TB TREATMENT WITH FOLLOW UP .SEND CULTURES AS FAR FOLLOW UP .SEND CULTURES AS FAR AS POSSIBLE OF POSSIBLE FOCAL AS POSSIBLE OF POSSIBLE FOCAL SITESITE

IF BY 8 WEEKS THERE IS NO IF BY 8 WEEKS THERE IS NO OBJECTIVE RESPONSE-CONSIDER OBJECTIVE RESPONSE-CONSIDER ALTERNATE DIAGNOSISALTERNATE DIAGNOSIS

Conradie F;Wilson D ..SAHIVCS Conradie F;Wilson D ..SAHIVCS journal ,June 2006.journal ,June 2006.

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