Transcript Final CPC Literature Review 03-06-2015

Dr. Ghazala Rasool
Senior Registrar
Medical Unit-II
Pyrexia of Unknown Origin
 In 1961 Petersdorf and Beeson defined PUO as:
 Fever higher than 38.3 °C (101 °F) on several occasions
 Persisting without diagnosis for at least 3 weeks
 At least 1 week's investigation in hospital
 A new definition which includes the outpatient
setting (which reflects current medical practice) is
broader, stipulating:
 3 outpatient visits or
 3 days in the hospital without elucidation of a cause or
 1 week of "intelligent and invasive" ambulatory
investigation
Pyrexia of Unknown Origin
 In 75% cases of PUO, cause can be determined with
detailed investigations. In rest, cause remains
uncertain.
 Infections and malgnancies account for most PUOs
(25-40% of cases each)
 Autoimmune/ rheumatological disorders account for
10-20% cases.
Adult Onset Still’s Disease
 Adult Still’s disease is an inflammatory disorder
characterized by:
Quotidian (daily) Fever
Arthritis
Rash
 It is uncommon, as observed in many published case
series.
 It has been recognized as an important cause of the
fever of the unknown origin (FUO).
History
• It is named after the English physician George Still (in
1896) who first described it in children.
 “Still’s disease” has become the eponymous term for systemic
onset juvenile idiopathic arthritis.
 In 1971,the term “adult onset still disease” was used to
describe a series of adult patients who:
 1. did not fulfill the criteria for rheumatoid arthritis
but
 2. who had features similar to the children with systemic onset
juvenile idiopathic arthritis.
ETIOLOGY
 Unknown
 A variety of infectious triggers have been suggested,
including:
 Viral pathogens,
 Yersinia enterocolitica and
 Mycoplasma pneumoniae
 It has also been suggested that genetic factors are
important, for example, human leukocyte antigen (HLA)B17, B18, B35, and DR2.
EPIDEMIOLOGY
 A retrospective French study estimated the annual incidence of ASD to be
0.16 cases per 100,000 people.
 In a large multicenter prospective study from tertiary care hospitals in
Turkey, Still’s disease has been identified as the most common non
infectious inflammatory disease causing FUO in about 13.6% of their
patients. 1
1. Kucukardali Y, Oncul O, Cavuslu S, Danaci M, Calangu S, Erdem H, Topcu AW, Adibelli Z, Akova
M, Karaali EA, Ozel AM, Bolaman Z, Caka B, Cetin B, Coban E, Karabay O, Karakoc C, Karan MA,
Korkmaz S, Sahin GO, Pahsa A, Sirmatel F, Solmazgul E, Ozmen N, Tokatli I, Uzun C, Yakupoglu G,
Besirbellioglu BA, Gul HC; Fever of Unknown Origin Study Group. The spectrum of diseases causing
fever of unknown origin in Turkey: a multicenter study. Int J Infect Dis. 2008 Jan;12(1):71-9. Epub 2007
Jul 12. PubMed PMID: 17629532.
EPIDEMIOLOGY
 An equal gender distribution.
 There is a bimodal age distribution, with:
• one peak between the ages of 15 and 25 and
• the second between the ages of 36 and 46.
 However, patients older than age 70 have been
reported.
CLASSIFICATION CRITERIA
 There is no specific test or combination of tests that
can be used to establish the diagnosis of ASD.
 At least seven sets of diagnostic criteria have been
proposed.
 However, the Japanese criteria, often termed the
Yamaguchi criteria, have the highest sensitivity in
patients with a definite diagnosis of ASD.
Major Criteria
Minor Criteria
Exclusion Criteria
Temperature > 39ºC
(102.2ºF) for >1 wk
Sore throat
Infections ,especially
sepsis
Leukocytosis
>10,000/mm3 ( 80%
granulocytes)
Lymphadenopathy and/or
Epstein-Barr infection
Typical Rash
Splenomegaly or
hepatomegaly
Malignancy
Arthalgias > 2wks
Abnormal liver function
studies, particularly
elevations in AST ALT
LDH
Inflammatory diseases
YAMAGUSHI CRITERIA
Negative tests for ANA and
rheumatoid factor
 AOSD should be considered if
 5 criteria (2 of which being major) are met.
 Once malignancies, infectious diseases and
rheumatological diseases have been excluded.
 The Yamaguchi criteria have a sensitivity of 96% and
specificity of 92%.
CLINICAL FEATURES
FEVER
 Daily fever
 It is usually quotidian or double-quotidian (two fever
spikes per day).
 The temperature swings can be dramatic, with changes of 4ºC
occurring within four hours.
 Complete defervescence is not required with these fevers, as
fever persists between spikes in approximately 20 percent of
cases.
RASH
 The classic rash is
 Evanescent
 Salmon-colored
 Macular or maculopapular eruption
 Transient that tends to occur with the fever.
 Predominantly involves trunk and extremities (rarely
involve the palms, the soles and face).
 The Koebner phenomenon may be present, in which the
cutaneous eruption can sometimes be elicited by
stroking the skin.
 The rash is frequently misdiagnosed as a drug
reaction.
Evanescent rash
Evanescent rash
MUSCULOSKELETAL
 Arthralgia, arthritis, and myalgia are universal features.
 Initially, the arthritis may be mild, transient, and
oligoarticular.
 However may evolve later into a more severe and
destructive polyarthritis
 Fusion of the wrist joints is characteristic.
 The most commonly involved joints, in descending order
are:
 Knees
 Wrists
 Ankles
 Elbows
 Proximal interphalangeal joints and shoulders
Clinical Features
 Pharyngitis
Sore throat was noted in 69 % percent.
 Lymphadenopathy
Slightly tender, enlarged cervical lymph nodes (one-half of patients).
 Splenomegaly / hepatomegaly
 Pleuropericardial effusions, transient pulmonary infiltrates in 30 to 40
percent of patients.
 Myocarditis is a rare complication
 Hematologic manifestations: pure red cell aplasia, DIC,
microangiopathic hemolytic anemia including, Reactive
hemophagocytic syndrome.
The Disease Complications
 It can include diverse complications, affecting multiple organ
systems.
 Moreover, the severity of the organ involvement can vary
considerably.
 The clinician should be alerted to the existence of life-
threatening AOSD complications, namely:
 The macrophage activation syndrome.
 Disseminated intravascular coagulopathy, thrombotic
thrombocytopenic purpura,
 Diffuse alveolar hemorrhage, and pulmonary arterial hypertension.
 Fulminat hepatic failure.
REACTIVE HEMOPHAGOCYTIC
SYNDROME
 It is termed as macrophage activation syndrome
when it occurs in AOSD.
 Rare but fatal complication, may be underdiagnosed.
 A retrospective study reported RHS in six (12 percent)
out of 50 AOSD patients.
REACTIVE HEMOPHAGOCYTIC
SYNDROME
 Hemophagocytic lymphohistiocytosis (HLH) is a
potentially fatal hyperinflammatory condition caused
by a highly stimulated but ineffective immune system
response.
 There is uncontrolled proliferation of T lymphocytes
and well-differentiated macrophages, leading to
widespread hemophagocytosis and cytokine
overproduction
The diagnostic hallmark of RHS
 is the presence on bone marrow examination of
numerous, well-differentiated macrophages
(histiocytes) that are engaged actively in the
phagocytosis of hematopoietic elements
The Clinical Presentation of Macrophage
Activation Syndrome (MAS)
 Is generally acute and occasionally dramatic.
 Typically, patients become:
 acutely ill with the sudden onset of non remitting high
fever,
 profound depression in all 3 blood cell lines,
 and elevated serum liver enzyme levels,
 development of DIC.
Other Conditions associated with
HLH
 HLH may also occur as a secondary disorder in
association with:
 severe infections,
 malignancies,
 rheumatologic disorders, and
 some metabolic diseases.
 This rare phenomenon was first ever diagnosed and
reported in our setup by our Dengue team in HFH,
caused by Dengue co infection with Malaria.
DISEASE COURSE
Monophasic pattern —
 Lasts only weeks to months, completely resolving within less
than a year.
Intermittent pattern —
 one or more disease flares, with complete remissions between
episodes lasting from weeks up to one or two years.
 Subsequent flares tend to be less severe and of shorter duration.
Chronic pattern —
 Persistently active disease, in which articular symptoms usually
predominate.
 A potentially destructive arthritis may occur in patients in this
group.
INVESTIGATIONS
 No specific test or combination of tests that can be used to
establish the diagnosis of ASD.
 Raised ESR an CRP are seen in virtually all patients
 Normocytic normochromic anemia is seen in the
majority of patients.
 Elevated ALT, AST , LDH are seen in 75 percent of
patients.
 Increased serum ferittin, exceeding 3000 ng/mL, is
seen in 70 percent of patients
INVESTIGATIONS (continued…)
 Immunologic studies — the absence of antinuclear
antibodies and rheumatoid factor is one of the minor
criteria for ASD.
 Bone marrow examination may reveal hyperplasia
of granulocytic precursors.
 Radiographic findings —
 nonerosive narrowing of the carpometacarpal and
intercarpal joint spaces of the wrists
 often progresses to bony ankylosis (40%).
Serum Ferritin
 Markedly elevated serum ferritin concentrations in as
much as 70 percent of patients.
 More likely to be a consequence of cytokine-induced
synthesis by reticulo-endothelial system or of hepatocyte
damage with increased release.
 Hyperferritinaemia is reported by some studies to be
associated with hisctiocyets hyperactivity
 The elevations correlate with disease activity.
 A serologic marker to monitor the response to treatment.
Glycosylated Ferritin
 Tends to be lower than in other rheumatic disease.
 It may remain low both in the active phase of disease
and in remission.
 Both marked hyperferritinemia and a low fraction of
glycosylated serum ferritin also occur in the
macrophage activation syndrome
 Both the total serum ferritin and the glycosylated
fraction provide more diagnostic specificity for
ASD than does reliance upon either test alone.
Predictors of Chronic Disease and
Unfavorable Outcome
1.
The development of a polyarthritis early in the course
of ASD.
2.
Involvement of the shoulders or hips.
3.
The need for more than two years of systemic
glucocorticoid therapy.
 Functional outcomes — The functional status of patients
with ASD is generally good, even in the setting of a chronic
disease pattern.
TREATMENT
 Therapeutic decisions should be based upon the
extent and severity of organ system involvement.
 The principal options for treatment are:
 NSAIDs
 Glucocorticoids
 Biologic agents
 DMARDs
NSAIDS
 Initial therapy with NSAIDs in patients with relatively mild
disease.
GLUCOCORTICOIDS
 If there is no response to several days of starting NSAID.
 Patients with debilitating joint symptoms, or internal
organ involvement should be started on glucocorticoids
from the outset of therapy.
 Pulse glucocorticoids may be employed initially in
patients with life-threatening manifestations such as:
 severe hepatic involvement,
 cardiac tamponade,
 disseminated intravascular coagulation
 HPS
 3BIOLOGICAL AGENTS
No response to NSAIDs and glucocorticoids within two to four
weeks.
 a)ANAKINRA (recombinant human interleukin-1 receptor antagonist
 b)RITUXIMAB (monoclonal antibody )
 c) TUMOR NECROSIS FACTOR (TNF) inhibitors —
Experience with TNF inhibitors remains limited to case reports
Promising results have been reported with etanercept,
infliximab
and adalimumab
4.DMARDS
•when patients have either not responded sufficiently to NSAIDs,
glucocorticoids, or biologic agents
 METHOTRAXATE (Its most common role is as a glucocorticoidsparing agent)
 CYCLOSPORIN
Adult Onset Still’s Disease in Pakistan
 A number of studies and cases have been published
internationally and also in Pakistan.
 A retrospective study was conducted at Agha Khan
Hospital Karachi (1995-2005) to study the clinical
characteristics of Stills disease in a tertiary care
hospital of Pakistan and compare it with similar
internationally published studies. 2
2. Abid N, Khalid AB. Adult onset Stills disease in a tertiary care hospital of Pakistan. J Pak Med
Assoc. 2009 Jul;59(7):464-7. PubMed PMID: 19579736.
Results
 13 patients with ASOD were identified.
 Fever (100%)
 Arthralgia, myalgia (100%)
 Sore throat (53.8%)
 None of these patients had rash with fever.
 Lab patterns were also studied which were consistent
with international data.
Conclusion
 Clinical characteristics of Stills disease in our
country are mostly similar to those seen in other
regions.
Atypical Presentations of Still’s Disease
Worldwide
 Different cases of atypical presentations of Still’s disease
have been reported worldwide, of which two are worth
mentioning.
 Interestingly a case of Fulminant hepatic failure in a
patient with newly diagnosed Stills disease has been
recently reported. 3
3. Nalini Valluru, Venkata S. Tammana, Michael Windham, Eyasu Mekonen, Rehana Begum, and
Andrew Sanderson, “Rare Manifestation of a Rare Disease, Acute Liver Failure in Adult Onset Still’s
Disease: Dramatic Response to Methylprednisolone Pulse Therapy—A Case Report and Review,” Case
Reports in Medicine, vol. 2014, Article ID 375035, 5 pages, 2014. doi:10.1155/2014/375035
 A case of an eosinophilic pleural effusion as a novel
and unrecognized manifestation of active Still’s disease was
reported in Greece in 2002. 4
4. Katerina M. Antoniou, George A. Margaritopoulos, Ioannis Giannarakis, et al., “Adult Onset
Still’s Disease: A Case Report with a Rare Clinical Manifestation and Pathophysiological
Correlations,” Case Reports in Medicine, vol. 2013, Article ID 981232, 4 pages, 2013.
doi:10.1155/2013/981232
Case Report
 A 39-year-old woman was admitted because of a non
itching macular-papular rash. In addition, the patient
complained of arthralgias, myalgias, fever of 38 degrees C,
and night sweats.
 On admission, a neutrophilic leukocytosis (23.6),
 An increase in C-reactive protein (185 mg/l),
 Ferritin level of 1,740 microg/l
 Liver enzymes were raised.
 Normal radiological and echocardiographic findings.
 Repeated blood cultures were negative.
 Antibiotic therapy was continued without any
improvement.




In addition, acetaminophen and ibuprofen were given.
Liver function worsened and an icterus developed.
A working diagnosis of Still's disease was made.
The patient was treated with high-dose methylprednisone
(250 mg/day for 3 days, then 100 mg/day).
 Liver biopsy revealed subacute hepatitis with necrosis and
accompanying cholangitis.
 The prednisone therapy induced a fast remission and
improvement of liver function, liver transplantation was not
necessary.
 The patient is, 16 months after the incident, without symptoms
under prednisone 3 mg/day, and the liver function is normal.
Conclusion
 Still's disease must be considered as part of the
differential diagnosis of acute liver failure, because an
early diagnosis and consequent therapy with
prednisone may prevent the need for liver
transplantation.
Still’s Disease: A Case Report with a Rare
Clinical Manifestation
 Pleuritis is the most common pulmonary
manifestation, and pleural effusions are usually
exudative with a predominance of neutrophils.
 A case of an eosinophilic pleural effusion as a novel
and unrecognized manifestation of active Still’s
disease was reported in Greece in 2002.
A 51-year-old woman with a 15 days history of:
 Chest pain on the left hemithorax, shortness of breath, evening fever





(38.5°C), and diffuse arthralgias.
On admission she was febrile (39.2°C) and tachypneic.
On physical examination there were findings of left sided pleural
effusion.
Laboratory findings included WBC count = 12000 cells, (ESR) =
33 mm/h.
Chest radiography revealed left sided pleural effusion.
Empiric treatment with broad spectrum antibiotics was commenced
immediately.
 Thoracocentesis revealed an eosinophilic pleural
effusion (EPE) (WBC = 5000, neutrophils = 38%,
lymphocytes = 30%, and eosinophils = 20%).
 A work up for diagnosis of EPE was undertaken.
 Blood, urine, and sputum cultures, stains and
cultures of bronchial wash obtained and tuberculin
skin testing were all negative for infectious causes.
 CT scan of chest and abdomen, ultrasound of
abdomen, mammography, and FOB ruled out the
presence of malignancy.
 CT pulmonary angiography was negative for
pulmonary embolism but revealed a mild right
pleural effusion as well
 Rheumatoid factor, antinuclear antibodies, were
negative.
 On the fifth day of admission the patient became
febrile again (39.4°C).
 There was no evidence suggestive for a connective
tissue disease.
 The most plausible diagnosis based on clinical and
laboratory findings and exclusion of other possible causes
of EPE was AOSD (total 4 Yamaguchi’s criteria, 3 major).
 The patient was treated with corticosteroids.
 She was discharged afebrile.
 Reevaluation after 3 and 6 months showed marked
improvement of the radiological and clinical findings.
Take Home Message!
In addition to common causes of PUO, there
are some uncommon causes as well and
Adult onset stills disease is an example in this
regard.