PYREXIA OF
UNKNOWN ORIGIN
Dr Henry Sunpath
Head of Medicine
Mc Cord Hospital
3 September 2009
Outline of presentation
 APPROACH
TO PUO
 PUO AND HIV
 LOOKING FOR OTHER CAUSES=NTS
 POST ART =FEVER
 PRE ARTRE= AND FEVER
MR B.S 28 years old

Admitted 7/10/07 with Fever and Nt sweats >
3/52 found to have pericardial effusion on US
scan and started emperically on TB tx also T/F
2 units of blood for normocytic anaemia Hb 5.6

Recent HIV test apparantly negative but result
not seen by our team

Given FU app for to assess response to tx
Readmitted 16/10

PC persisting fevers and nt sweats with
continued wt loss

OE Pale, pyrexic small mobile LN lt posterior
cervical area
No rash, joints NAD, RS,ABDO NAD
Soft PSM dynamic cardiac pulsation
Pulse 104 BP 115/65
Neurological OE Normal




Investigations
 FBC:
Hb 7.38 Mcv 78
ESR 142

Wcc 18.6 Neut 15.7 Lym 2.19

Plats 557
 Film : Hypochromic,microcytic
 UE: 131,3.6,102,26,3.6,74
 LFT: NAD Alb 18
 CXR: Normal Urinalysis NAD
Working diagnosis
 1:
Bacterial endocardtis
 2: TB with slow response to tx
 PLAN
started on high dose penicillin and
gentamicin awaiting blood cultures
 TB tx continued
 Sent for echo and US at Parklands
 ABDO
US : Mild Splenomegaly otherwise
NAD with no nodes seen
 ECHO
: slightly dilated LV Good LV
function , small pericardial effusion 0.8 mm
 No vegetations or valve lesions seen
 Blood
culture Negative
Continued investigatons
 Bone
marrow: hypocellular marrow with no
evidence of infiltration ,constistent with
combined nutrional deficiency and
systemic illness
 Malaria and widal negative
 WR negative
 C3 + C4 Normal awaiting ANF
 Lymph node histology =Follicular
hyperplasia non specific finding
Progress
 Completed
10/7 of iv AB and continued
TB treament but spiking fever persisted
 Patient
becoming increasingly despondant
on ward and allowed to go home with FU
 Declined further HIV test while on ward
despite counselling

Problem list
 P.U.O
 Pericardial
effusion
 Mild LV dilatation
 Mild splenomegaly
 Anaemia [microcytic]+hypocellular marrow
 Neutrophil leucocytosis
 Hypoalbuminaemia
Possible Diagnoses
 Infective:
Pulmonary/ Extrapulmonary TB

Mycobacterium avium [MAI]

MDR TB

Disseminated fungal

CMV
 Malignancy: Lymphoma
 Collagen vascular diseases
 Granulamatous : sarcoid
Future plans on review






? CT SCAN of Chest and Abdomen looking for
lymphoma or hidden abscess collection
? Try pericardial tap for culture and cytology
? Further biopsy ie Liver
Repeated Blood cultures specifically looking for
TB,Fungal inf etc
Serological tests for CMV
Any other ideas? [need to confirm HIV status]
Fever of unknown origin
 Classic
PUO
investigation
 Nosocomial
3/52 Fever + 1 week of
3/7 OF IX
 Neutropenic 3/7 OF IX
 HIV asociated 4/52 OPD 3/7 inpatient
CAUSES CLASSIC PUO
 INFECTIVE
20-30%
 CANCER
10-20%
 AUTOIMMUNE 15-20%
 MISC
15-25%
 UNDIAGNOSED 5-10%
INFECTIVE
 Localised
pyogenic infection
 Systemic bacterial eg typhoid
 Mycobacterial MTB,MAI
 Fungal eg cryptococcus
 Viral eg HIV,CMV
 Parastitic eg Malaria,Toxoplasmosis
 Rickettsial eg Q fever
CANCERS
 LYMPHOMA
 LEUKAEMIA
 LIVER,RENAL,COLON,PANCREATIC
 SARCOMA
 ATRIAL
MYXOMAS
Collagen vascular diseases
 SLE
 RA
 PAN
 WEGENERS
 STILLS
 Polymyalgia
rheumatica
 Rheumatic fever
 Behcets
MISC
 GRANULOMATOUS
 DRUG
ie Sarcoid ,Crohns
induced fever
 ENDOCRINE ie
thyrotoxicosis,phaeocrocytoma
 INTRACERBRAL ie SOL,pontine
CVA,encephalitis
 METABOLIC /INHERITED ie familial
mediteranian fever
 Tissue infarction ie Post MI, Rec PE
HIV associated PUO
 HIV
alone
 TB,M avium/intracelulare
 Toxoplasmosis
 CMV ,PCP ,Salmonella
 Cryptococcus,Histoplasmosis
 Non Hodgkins Lymphoma
 Drug induced
 OTHER
CAUSES ASSOCIATED WITH
FEVER=TTP/HUS
 Non
Typhoid salmonella…the need to
screen in SAVER=TTP/HUS,
 Look
for candidemia as a cause of PUO
in ICU pts-
Nomenclature
 DNA
hybridization studies show that
medically important Salmonellae
organisms can be considered as a
single species known as Salmonellae
enterica
S. typhi
S. paratyphi
>2000 remaining
Nontyphoid
serotypes
•Grouped as NTS

Background- Salmonellae
infection in HIV infected African
adults
Pattern of HIV related disease seen in Africa is known to
be different from that seen in the developed world. (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)



NTS septicaemia is one of the most frequent
manifestations of HIV in adults in Africa.
Most case series have found that focal metastatic NTS
infections in HIV are rare


Bacterial infections and TB predominate
Case reports of focal infection in literature
Pulmonary involvement in HIV patients with NTS
bacteraemia is well recognised

May represent isolated NTS lung disease or co-infection
with second respiratory pathogen
Pattern of Bacteremia in HIV
Positive African adults

NTS as a common cause of bacteraemia illness in HIVpositive patients is now an established pattern in HIV
endemic areas of Africa. (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)

This pattern is distinct from that seen in HIV-positive
patients in Europe or North America.


Greater proportion of total isolates are Gram-postive, and
S. aureus is the most common organism
• Related to either IV drug use or intravenous access
devices
Gram-negative isolates from smaller proportion of total
• NTS are commonest group of organisms
Clinical Course of NTS
bacteraemia in HIV-Positive
African Adults
 Non-typhoidal
salmonella bacteraemia
among HIV-infected Malawian adults: high
mortality and frequent recrudescence.
AIDS 2002.


Prospective study that enrolled 100
consecutive adult inpatients with NTS
bacteraemia
Patients Treated with chloramphenicol and
survivors followed to detect recurrence.
Microbiological findings
 NTS




blood isolates from 100 cases
75 – S. typhimurium
19 – S. enteritidis
1 – S. typhimurium + S. enteritidis
5 – other Salmonella spp.
Host Susceptibility for
Salmonellosis


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





Extremes of age
Alteration of bowel endogenous bowel flora
Diabetes
Malignancy
Rheumatological disorders
Reticuloendothelial blockage

From Malaria or sickle cell disease
Therapeutic immunosuppression of all types
HIV infection
Anatomic disruptions

Kidney stones, urinary tract abnormalities, gallstones,
atherosclerotic endovascular lesions, schistosomiasis, and
prosthetic devices may serve as foci for persistent Salmonella
infection
Focal NTS infection- Case
Reports

Focal infections due to non-typhi Salmonella in patients
with AIDS: report of 10 cases and review. Clin Infec Dis.
1997 Sep; 25(3):690-7



Ten of 38 HIV-infected patients (26.3%) with salmonellosis
documented over a period of 9 years had focal suppurative
complications
Infections of the urinary tract, lungs, and soft tissue,
followed by arthritis, endocarditis, and meningitis were
most frequently seen
Infectious endocarditis due to non-typhi Salmonella in
patients infected with human immunodeficiency virus:
report of two cases and review. Clin Infect Dis. 1996
May;22(5):853-5
Focal NTS infection- Case
Reports

Salmonella pyomyositis in patients with the human
immunodeficiency virus. Br J Rheumatol. 1995 Jun;
34(6):568-71
 Salmonella septic arthritis in HIV patients. Br J
Rheumatol. 1993 Jan;32(1):88
 Nontyphoidal salmonella intracranial infections in
HIV-infected patients. Clin Infec Dis 1997, 25:11181120.
 Non-typhi Salmonella adrenal abscess in an HIVinfected patient. Case Reports.
 Liver abscess due to Salmonella enteritidis in a
returned travelor with HIV infection: case report and
review of the literature. Rev. Inst. Med. Trop. S.
Paulo. March-April, 2003;45(2): 115-117
Lung Involvement in HIV-positive
Patients
 Salmonella
Lung Involvement in Patients
with HIV Infection. CHEST1997.

Retrospective clinical study- studied records
of all HIV-infected patients with Salmonella
bacteraemia at a university tertiary hospital in
Spain from Jan 87 to Dec 95.
Findings

Lung involvement was frequent





Present in 35% of HIV positive patients with NTS
bacteraemia
33% of those with lung involvement had definite
Salmonella pulmonary infection
Predisposing factors for focal disease were not
apparent
Focal lung involvement with NTS was not associated
with worse prognosis
56% of those with lung involvement had
Superinfection with other respiratory pathogen



28% PCP
17% pyogenic bacterial infections
11% TB
Antimicrobial Susceptibility and
Resistance

In developed countries there is great concern over development of antimicrobial
resistance


Nairobi, Kenya


48%-56% of isolates were resistant to 3 or more of the routinely available antimicrobials
Malawi






Increase in fluroquinolone resistance among Salmonellae serotypes
5% resistant to chloramphenicol
73% resistant to co-trimoxazole
79% resistant to ampicillin
43% resistant to gentamycin
40% resistant to tetracycline
Bangui in Central Africa (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)




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12% resistant to chloramphenicol
75% resistant to co-trimoxazole
80% resistant to amoxicillin
26% resistant to gentamycin
56% resistant to tetracycline
0% resistant to ceftriaxone
0% resistant to ciprofloxacin
Conclusions
 Blood
stream infections (BSI) with NTS
are a major cause of morbidity and
mortality in African patients with HIV.
 Treatment should be initiated empirically
before final bacteriological results are
available
 Knowledge about type of pathogens
responsible for BSI and pattern of
antibiotic resistance is key
Conclusions
 Consider


NTS in Pt with
HIV, CD4 <200, or clinical evidence of HIV
and p/w fever and GI symptoms, or
respiratory involvement or fever of
unknown origin
 Empirical
treatment with
chloramphenicol, ceftriaxone,
ciprofloxacin appears appropriate

High resistance to penicillins
 ARV

treatment also prevents recurrence
Sidovudine has been shown to protect
against Salmonellae bacterial recurrence
IRIS AND FEVER
35 yo M with HIV infection
HPI:
 June 2006: Diagnosed HIV (+) in the
setting of PCP. CD4 cell count: 9.
 July 28: Presented to begin ARVs. Pt
complained of nausea and chronic
diarrhea. Began D4T/3TC/EFV. Pt had
an abnormal CXR thought to represent
resolving PCP infection.
 Aug 10: Pt complained of nausea and
vomiting and was treated with
metoclopromide.

Aug 21: Admitted with worsening nausea,
vomiting and diarrhea. He noted loss of weight
of 6 kg over 1 month. Unremarkable CXR
(results not available). No AFB + sputum.
Ultrasound showed 'splenic granulomas' but
no abdominal lymphadenopathy. Pt was
diagnosed with IRIS tuberculosis and he
commenced standard combination antituberculosis therapy. Pt reportedly responded
well clinically.
 Sept 12: Complained of persistent nausea and
vomiting at outpatient visit.
 Oct 3: Admitted with delirium, fever & vomiting
for 1 week

Sodium 124 mmol/l; creatinine 80 mmol/l.
 Lumbar puncture:


16 lymphocytes/mm3, neutrophils 2/mm3, red
blood cells 30/mm3. India Ink (+), gram stain (-).
Protein 1.24 g/l, glucose 1.5 mmol/l. Cryptococcal
CSF antigen (+).
Diagnosed with IRIS cryptococcal meningitis
 Treated with amphotericin, continued
antiretrovirals, cotrimoxazole and antituberculosis therapy.
 Became afebrile and mental status improved.
Discharged on to chronic care facility to
complete therapy. Received therapeutic
lumbar punctures to manage intracranial
pressure (never formally measured).

Oct 20: Completed 14 days of amphotericin;
changed to fluconazole 400 mg daily.
 Oct 24: Switched to AZT/3TC/EFV due to
severe peripheral neuropathy. Pt remained
at chronic care facility without fever but with
"dull mental status," vomiting and
hyponatremia. Thought to be clinically
dehydrated and received intravenous fluids.
 Nov 2: Repeat CD4 5, VL unavailable.
 Nov 6: Clinically he failed to improved and
developed neutropenia w/ decreased
hematocrit of 23% but preserved platelets of
214 cells/ul. He died on Nov. 7 at chronic
care facility.
Differential diagnosis of worsening
of symptoms after HAART therapy
Patient with OI
Treated with ART
Asymptomatic
immune
recovery
Return of original
symptoms
Relapse
IRIS
New Symptoms
New OI
Medication
Side-effects
IRIS
Proposed Diagnostic Criteria for IRIS
(Adapted from: ACTG 2006, Shelburne et al, 2002; French et
Required Criteria
al 2005)
 Worsening symptoms of
Supportive Criteria
inflammation/infection,
 Increase in CD4+ count of
disease progression or
>25 cells/ｵL
enlargement of pre-existing
 Atypical presentation of
lesions after definate clinical
“opportunistic infections or
improvement with antitumours”
microbial therapy preHAART
 Biopsy demonstrating
 Temporal relationship with
granulomatous
starting antiretroviral therapy
inflammation or unusually
exuberant inflammatory
 Symptoms not explained by
response
newly acquired infection or
disease, or the usual course
 Spontaneous resolution
of a previously acquired
without specific
disease
antimicrobial therapy

Decrease in HIV RNA level
by >1 log10
Immune Restoration OI
Manifestations Are Often Atypical
MAC
Lymphadenitis
CMV
C. neoformans
Pleocytosis
Hepatitis C
ALT
Hepatitis B
Focal
Vitreitis, Uveitis
Marked
↑HCV RNA &
↑HBV DNA
CASE 1: M. TB Immune
reconstitution

28 Black African female 24/40 gravid
diagnosed with pulmonary tuberculosis
and HIV positive in July 2002
 Living with sister and 6 year old son
 recently in Zambia 3/12 contact with brother
who had just died of TB
Presentation
•
•
•
•
•
•
3/52 - SOB, cough, fevers, weight
loss
Febrile temp 40 0C
Cachectic; Left upper lobe crepitations
Baseline CD4 cell count 59 (11%) and
HIV RNA viral load of 266,700
copies/ml
Inadequate sputum sample;
Bronchoscopy – BAL AFB negative
(AFB culture positive)
CXR – dense L hilum
Many Pathogens and Syndromes
Infectious
Pathogens
 M. tuberculosis
 M. avium complex
 Cryptococcus
 Pneumocystis
 Cytomegalovirus
 Herpes simplex
 Histoplasmosis
 Hepatitis B and C
•
•
•
•
•
•
•
Auto-immune
Herpes zoster
PML (JC virus)
Kaposi’s sarcoma
(HHV8)
M. leprae
Bartonella
Leishmania major
Chlamydia
trachomatis
Adapted from French et al, AIDS 2004
•
•
•
•
Grave’s disease
SLE
Sarcoidosis
Guillain Barre
Epidemiology of IRIS (CID
2000;30:882)
•
Now >300 case series and reports in English
literature
35
30
25
20
%
15
10
5
0
TB
i
p
o
s
u
c
n
c
M
e
o
c
.x
to
M
p
y
Cr
AC
V
CM
V
B
H
V
C
H
Immune Reconstitution Syndrome:
Clinical Settings
1. “NEW” INFECTION
CD4 <200, start ART MAC lymphadenitis
2. “EXISTING”INFECTION
DX CMV retinitis
start ART CMV immune vitriti
FEVER BEFORE STARTING
HAART
 History
-34 yr old women tested HIV
positive in Dec 2005.
 Presented in Jan 2006 to GP with
oesophageal candidiasis and a history of
cough with occasional loose stools since
Nov 2005.She also had 8 kg wt loss over
tst 6 months..No other OI or HIV related
illness
 EXAMINATION
T-38.5 WITH SINUS
TACHYCARDIA,WASTING,PALLOR AND
SEVERE ORAL TRUSH.
 NO LN,LIVER OR SPLEENIC
ENLARGEMENT.
 RESPIRATORY EXAM =NORMAL
INVESTIGATIONS
 Hb
-6.9 g/dl NNA
 WCC 5.6 AND PLT -88
 CD4-27 and VL=>750 000
 S.Alb-22g/l
 LDH 3116
 LFT otherwise normal
 Blood cultures –aerobic and anaerobic
mycobacterial negative
 Bone
marrow trephine and aspiratedisordered erytropoeisis in keeping with
HIV disease,Histology of the trephine-no
granulomas or signs of malignancy.
 The CXR was normal.
Futhur course
 Treated
with Diflucan and given blood
transfusion.
 ART commenced Reg 1 a.
 Symptomatic peripheral peripheral
neuropathy after 2 weeks-change to AZT.
 Four weeks later clinical deterioration with
confusion and pallor but no fever.
 CXR=R pleural effusion-blood stained
 CYTOLOGY=high grade plasma blastic
NON HODGKINS LYMPHOMA
 Refuse futhur treatment after assesment
DISCUSSION
 Dillemma
for clinicians of pt presenting
with advanced HIV infection for the first
time with prominent constitutional
symptoms.Careful evaluation for Ois is
unrevealing.Within weeks of nstarting ART
a fatal disease process becomes apparent
 Advanced HIV infection can produce fever
and wt loss /constitutional symptoms
without underlying OI.However this is a
diagnosis of exclusion
 These should be approached as PUO
 Various
forms of TB are the most common
causes of PUO.If cough is present then
sputa should be sent for AFB stains.
 Other initial investigations should be
 FBC,WITH DIF COUNT
 LFT
 CRP
 URINE ANALYSIS-WBC CASTS ?culture
 CXR
 ULTRASOUND
HEART/ABDOMEN to
look for effusions/fluid,lymph
nodes,hepatic annd splenic lesions and
pelvic masses.
 TB IS SUGGESTED Bypulmonary
infiltrates,fluid colections
,lymphnodes,splenic lesions,
 OTHER INFECTIONS AND
MALIGNANCIES CAN ALSO PRESENT
LIKE THIS!
 MYCOBACTERIAL
BLOOD CULTIRES
may be used to using the BACTEC/Myco
/F lytic bottle TO DETECT
BACTERIA,FUNGI ,NORCADIA as well
as MTB and MAC and ?MOTT
 CSF studies –CRAG /India ink
 BMAT-if bicytopenia or pancytopenia
present
 Liver biopsy if ALP and GGT raised.
 LN-FNAC or biopsy (normal saline and
formalin)
 EMPERICAL
TB TREATMENT WITH
FOLLOW UP .SEND CULTURES AS FAR
AS POSSIBLE OF POSSIBLE FOCAL
SITE
 IF BY 8 WEEKS THERE IS NO
OBJECTIVE RESPONSE-CONSIDER
ALTERNATE DIAGNOSIS
 Conradie F;Wilson D ..SAHIVCS journal
,June 2006.
References
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Chehimi J, Starr SE, Frank I et al. Impaired interleukin 12 production in human immunodeficiency
virus-infected patients. J Exp Med 1994; 179:1361-1366
Casado JL, Navas E, Begona F, Moreno A, Martin P, Hermida JM, Guerrero A. Salmonella Lung
Involvement in Patients with HIV Infection. Chest 1997, 112:1197-1201
Casado JL, Valdezate S, Calderon C, Navas E, Frutos B, Guerrero A, Martinez-Beltran J.
Zidovudine Therapy Protects against Salmonella Bacteremia Recurrence in Human
Immunodefieciency Virus- Infected Patients. J of Infec Dis 1999, 179: 1553-6
Gilks CF, Brindle RJ, Otieno LS, Simani PM, Newham RS, Bhatt SM, Lule GN, Okelo GB,
Watkins WM, Waiyaki PG, et al. Life-threatening bacteremia in HIV-1 seropositive adults admitted
to hospital in Nairobi, Kenya. Lancet 1990, 336(8714):545-9
Gordon MA, Banda HT, Gondwe M, Gordon SB, Boeree M, Walsh AL, Corkill JE, Hart CA, Gilks
CF, Molyneux ME. Non-typhoidal salmonella bacteraemia among HIV-infected Malawian adults:
high mortality and frequent recrudescence. AIDS 2002, 16: 1633-1641
Gordon MA, Walsh AL, Chaponda M, Soko D, Mbvwinji M, Molyneux ME, Gordon SB. Bacteremia
and Mortality Among Adult Medical Admissions in Malawi- Predominance of Non-typhi
Salmonelllae and Streptococcus pneumonia. J of Infec 2001, 42: 44-49
Hart CA, Beeching NJ, Duerden BI. Infections in AIDS. J Med Microbiol 2000, Vol 49: 947-967
Hohmann EL. Nontyphoidal Salmonellosis. Clinical Infectious Disease 2001, 32:263-9
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
Vazquez-Torres A, Jones-Carson J, Baumler AJ et al. Extraintestinal dissemination of Salmonella
by CD18-expressing phygocytes. Nature 1999; 401:804-808