دكتر مژگان هاشميه

فوق تخصص خون اطفال

ÒFever of Unknown Origin

Ò  Terminology

Ò  Fever > 38.3^oC (101 ^oF) on several occasions.

Ò  Illness of more than 3 weeks’ duration.

Ò  Uncertain diagnosis after 1 week of study in the hospital.

Ò  Etiology

Ò  Infection 30-50%

Ò  Collagen vascular disease 10-20%

Ò  Neoplasms 5-10%

Ò  Miscellaneous 10-20%

Ò  No diagnosis 10-25%

Ò  Infectious Causes of FUO

Ò  Mononucleosis (EBV & CMV)

Ò  Systemic viral syndrome

Ò  Urinary tract infection

Ò  Intra-abnominal and Retroperitoneal Abscesses

Ò  Osteomyelitis

Ò  Respiratory tract infection

Ò  Tuberculosis

Ò  Bacterial meningitis

Ò  Endocarditis

Ò  Enteric infection

Ò  Malaria

Ò  HIV infection

Ò  Non Infectious Cause FUO

Ò  Miscellaneous

          Drugs and nutritional supplements

          Pseudofever disorders

          Pulmonary embolism

          Hyperthyroidism

          Kawasaki disease

Ò  EVALUATION OF OUR PATIENT

Ò  CBC=ß  thal minor

ESR=140
CRP=9.6

PBS(MALARIA&BORRELIA)=NEG

Ò  SGOT=40
SGPT=31
ALK.P=355
LDH=380

TG-CHOL-LDL-HDL=NL

Ò  C3=NL ,
 C4=NL ,
CH50=NL
ANA=NL  ,
C-ANCA&P-ANCA=NL
anti ds-DNA=negative
anti cardiolipin=negative
anti phospholipid=negative
R.F=negative

Ò  Blood Culture: NEG
BACTEC: NEG
U.A: NL , U.C: NEG
CSF.A&CSF.C: NL
CSF(TB PCR-ADA-WRIGHT): NL
ASO.TITER: NL
FIBRINOGEN: NL
immunE  electrophoresis: NL

Ò  BRUCELLA SEROLOGY:NEG
IFA KALA AZAR:NEG

viral serology(hbv &hcv&HIV):NEG
 

Ò  BM aspiration& biopsy:NL
BM flow cytometry:NL
CD25=NL
skin biopsy:
chronic  lymphocytic vasculitis

Ò 
sonography:mild splenomegaly+accesory spleen
spiral CT scan(chest and abdominopelvic):
mild splenomegaly
bone scan:NL
chest X-ray:NL

Ò  FMF Assay

ÒTEST NO 1:

ÒThe  test is based on strip assay technique using genomic DNA. The assay covers  12mutions in the MEFV Gene as:

ÒE148Q,P369S,F479L,M680I(G/C),M680I(G/A),I692del,M694V,M694I,K695R,V726A,A744S,R761H.

ÒResult=Negative

ÒTEST NO 2:

ÒThe test is based on direct DNA sequencing for exon1,2,3,4,5,6,7,8,9,10 of the Mediterranean fever gene.

ÒResult= This individual has heterozygote mutation(R202Q) in exon2 of the MEFV gene

ÒFAMILIAL MEDITERRANEAN FEVER

q FMF is an autosomal recessive disorder

q characterized by brief acute, self-limited episodes of fever and polyserositis that recur at irregular intervals

q associated with development of amyloidosis.

Etiology

q The gene responsible for FMF is mapped on 16p13.3. It is designated MEFV.

q This  gene  encoding a  protein known as pyrin  which is expressed in myeloid cells.

q  Exon 10 and exon 2 carry most FMF-associated mutations.

q To date, more than 70 mutations have been discovered, mostly missense mutations.

q The 5 most common mutations (M694V, V726A, M694I, M680I, E148Q) are found in more than 2 ∕ 3 patients with FMF.

q Approximately 70% of patients with clinical manifestations

of FMF are heterozygous

q The most common missense mutation is M694V (substitution of methionine with valine at codon 694)

q occurs in 20-67% of cases

q Associated  with a greater disease severity and a higher incidence of amyloidosis

q It is also associated with increased risk for onset at an early age

Pathogenesis

q The exact pathogenesis of the acute episodes of FMF is unknown.

q Between episodes, patients with FMF have increased serum levels of interferon-γ and enhanced production of other proinflammatory cytokines, such as TNF-α,  IL-1β,  IL-6, and  IL-8, in circulating  leukocytes.

q Pyrin acts as an anti-inflammatory factor by inhibiting processing of pro-IL-1 β cytokine to the active form.

q The defective (or mutated) pyrin found in patients with FMF is functionally inactive.

q  As a consequence, stimulation of IL-1β processing and secretion occur, resulting in increased IL-1β levels that are responsible for the uncontrolled inflammation .

q Another possibility that was previously more popular is  C5a inhibitor deficiency in  patients with FMF.

q C5a is a fragment of complement, an anaphylatoxin, and a potent chemotactic agent .

q The hypothesis is that a deficiency of C5a inhibitor, which is a consequence of pyrin dysfunction in patients with FMF, allows further accumulation of C5a, leading to the acute attack.

Clinical Manifestations

q The onset of clinical manifestations occurs before 5 yr of age in

65% of cases and before 20 yr of age in 90% of cases.Onset

may be as early as 6 mo of age.

q  Exercise, emotional stress, infection, menses, and surgery may precipitate acute episodes.

q The  typical acute episode lasts 1-4 days

q includes fever and 1 or more symptoms of :

q sterile peritonitis, manifested as abdominal pain (90%)

q  arthritis or arthralgia (85%)

q pleuritis manifested by chest pain (20%)

Other manifestation:

a)     Erysipelas-like rash

b)     myalgia

c)     splenomegaly

d)    scrotal involvement 

e)     neurologic involvement

f)      Henoch-Schonlein purpura

g)      hypothyroidism

Diagnosis

q Genetic testing for the FMF gene confirms the diagnosis of FMF.

q Genetics laboratories usually screen for only the 10 to 15 most common mutations, and thus, rare mutations will be missed.

q Therefore, the diagnosis of FMF is still based on clinical manifestations, with genetic testing used as a confirmatory test .

Treatment

q Attacks of FMF can be prevented by prophylactic colchicine

(0.02-0.03 mg/kg/day; maximum 2 mg/day) .

q   65% of patients experience remission of attacks

q 20-30% experience improvement with significant reduction in the number and severity of the episodes

q 5-10% show no response.

q Colchicine therapy  decreases the probability of development of amyloidosis.

q  Poor compliance is common,owing to gastrointestinal side effects .

q Toxic effects (acute myopathy and bone marrow

hypoplasia) can be seen with doses >0.1 mg/kg, resulting in lethality at a dose ≥0.8mg/kg.

It has also been shown that biologic treatments,

especially the IL-1 inhibitor anakinra, produce a beneficial response in cases of FMF that do not respond to colchicine.

Complications and Prognosis

In 30-50% of untreated children and in 75% of adults with FMF, a form of renal amyloidosis develops .

Renal disease manifests as proteinuria that progresses to nephrotic syndrome and renal failure .Transplantation may be required for renal failure.

Mortality

Mortality from FMF usually results from complications of renal failure and amyloidosis, such as infection, thromboembolism, and uremia.

دكتر رضا شياري

فوق تخصص روماتولوژي اطفال

معرفي كيس:خانم دكتر مهسا مهري

رزيدنت بيمارستان امام حسين

پاسخ:

تشخيص هاي افتراقي:

خانم دكتر سيما بهرامي

رزيدنت بيمارستان مفيد

�     معرفی یک مورد تب طول کشیده

�     شکایت اصلی (chief complaint): تب طول کشیده به همراه ضایعات پوستی

�Present illness:بیمار دخـتر 8 سـاله ای اسـت که در تـاریخ  3 مـرداد 90 به عـلت تـب و ضایعات پـوستی بستری گردید تب وی حدودا از 40 روز قبل آغاز  شده و بجز علایم کوریزا در ابتدای تب، نکته دیگری نداشته است . طی دو نوبت مراجعه سرپایی تحـت درمان با کلیندامایسین و پنیسیلین قرار می گیرد، امـا تب وی همچنان ادامه می یابد. در طی دومین هفته بیماری، بیمار دچار لرزهای تکان دهنده میشود و ضایعات پوستی ابتدا در اندام فوقانی و سپس اندام تحتانی و باسن ایجاد می شود .  وی جهـت بـررسی در یـک مـرکز خصوصی بستری میشـود و در طی 18 روز بستری در آن مرکز تحت آزمایشات مختلف قرار میگیرد که یافته های مهم  درCBC  شامل آنمی ، ترومبوسیتوپنی، بالا بودن ESR,CRP  ودر سونوگرافی وجود اسپلنومگالی خفیف بود.

�  وی در طـی بسـتری در آن مرکـز تحـت درمان با کوتریموکسازول قرار گرفـت و به عـلت عـدم قطع تـب داروهـای وی به  سفتریـاکسون + وانـکومایسین تغییر یـافت و نهایتاً  پالس متیل پردنیزولون و IVIG دریافت کرد.به دنبال این درمان تب بیمار قطع میشود و بیمار با داروی استامینوفن مرخص می شود به مدت 2 روز بـدون تب بوده اما راش پوستی هم چنـان وجود داشته است.
با شروع مجدد تب و با شک به بیماری لانگـرهانس هیستیوسیتوز، در بخش  اطفال  جهت بررسی بیشتر بستری می شود

�     در زمان بستری حال عمومی بیمار خوب بود.

�     علایم حیاتی: 
38.6= AT درجه سانتی گراد      
10.5/7BP=سانتی مترجیوه         
18=RR در دقیقه    
110=PR در دقیقه

�     در معاینه فیزیکی:

معاینه چشم نرمال بود. معاینه ENT  نرمال بود. لنفادنوپاتی در هیچ قسمتی از بدن نداشت. معاینه قلب و ریه نرمال بود. معاینه شکم نرمال و بدون ارگانومگالی بود. معاینه تناسلی نرمال بود. معاینه عصبی نرمال بود. در پوست، راش اریزپل مانند، گرم، تندر، بدون خارش و پوسته ریزی با اندازه های متفاوت و حد اکثر 4*3 در انتهای اندام تحتانی، شکم و باسن وجود داشت.

�     سابقه قبلی و سلبقه فامیلی:

�  بیمار حاصل زایمان طبیعی، بدون سابقه قبلی بیماری و بستـری است. والـدین منصوب نبوده،  مادر سابقه تالاسمی مینور دارد. فرزند دیگر پسر 12 سـاله و سالم است. سـابقه مسافرت اخیر نمیدهد.

�     بعد از بستری آزمـایشـات زیر جهت بیمار انجام شد که نتایج به این صورت میباشد:

Problem list

� Fever and shake

� Erisiploid, painful and warm rash

� Anemia

� Thrombocytopenia

�    ESR

�     CRP

� Skin biopsy     chronic lymphocytic vasculitis  

� Splenomegaly

lymphocytic vasculitis

� lymphocytic vasculitis is defined by necrotizing destruction of blood vessel in the setting of lymphocytic inflammation in and around the vessel wall. It may evolve over time into a granulomatous pattern.

Drug reaction

� Positive finding:

� Skin lesion

� Negative finding:

� No history about use of any drug before beginning of disease

Connective tissue disease

� SLE

SLE Is a chronic autoimmune disease characterized by multi system inflammation and the presence of circulating auto antibodies directed against self antigens.

� Positive finding:

� Fever

� Cutaneous vasculitis

� Thrombocytopenia

� Anemia

� Splenomegaly

SLE

� Negative finding:

� ANA : negative

� C3- C4- CH50: NL

� Anti dsDNA: NL

� Anti phospholipid: NL

� Anti CARdiolipin: NL

Behcet’s

� Behcet’s is an autoinflamatory multi system disorder originally described as recurrent oral and genital ulceration associated with relapsing iritis or uveitis and is often characterized by cutaneous, arthritic, neurologic, vascular, gastrointestinal manifestations.

� The international study group criteria for diagnosis of Behcet’s are oral ophthus that recur at least 3 times within 12 mo accompanied by 2 of the following:

�  recurrent genital ulceration

� Eye lesions (anterior or posterior uveitis or retinal vasculitis

� Skin lesion (erythema nodosum, pseudofuliculitis or acneiforme nodules

� Positive pathergy test result.

� Positive finding:

� Skin lesion

� Negative finding:

� No history of oral or genitalia ulcer

Infections

� Herpes virus:

The hallmarks of common HSV infections are skin vesicle and shallow ulcers. Lesions begin as grouped erythematous papules that progress to vesicles. Pustules, ulcers and crusts and then healing without scanning in results in multiple discrete lesions and involves a larger surface area recurrences are sometimes associated with local edema and lymphangitis or local neuralgia.   

HSV

� Positive finding:

� ------

� Negative finding:

� Type of skin lesions, no history about vesicle lesion 

Ricketsial infection

� Rocky mountain spotted fever:

RMSF is the most frequently identified and most severe rickettsial disease in the USA.

RMSF should be considered in the deferential diagnosis of  fever, headache and rash in the summer months specially after tick exposure.

The illness is initially non specific with symptoms including headache, anorexia myalgia, restlessness pain and tenderness of calf muscle, GI symptom including nausea, vomiting, diarrhea, abdominal pain occur commonly early in the disease.

Rash usually appear only after 2 -4 days of illness.

Other symptoms including central nervous system infection, pulmonary disease, hepatosplenomegaly.

 confirm RMSF actually must be based on compatible epidemiologic, clinical and laboratory features.

Definitive diagnosis is most often accomplished by serology. The gold standard for diagnosis is a 4 – fold increased in IgG antibody titer (IFA)

RMSF

� Positive finding:

� Fever

� Rash

� Splenomegaly

� Negative finding:

� IFA: negative 

Mediterranean spotted fever

Typical finding include fever, headache, myalgia and macula popular rash that appears 3-5 days after onset of fever

Diagnosis of MSF is the same as that for RMSF.

MSF

� Positive finding:

� Fever

� Rash

� Negative finding:

� IFA: negative 

Typhus group rickettsioses

� Murine typhus

The incubation period varies from 1-2 w

Symptoms including rash, myalgia, vomiting, cough, headache and diarrhea or abdominal pain, hepato splenomegally and lymphadenopathy are reported often among children

Murine typhus

Diagnosis must be based on clinical suspicion. Confirmation of the diagnosis is usually accomplished by comparing acute and convalescent phase antibody titer obtained with the IFA.

Murine typhus

� Positive finding:

� Fever

� Rash

� Splenomegaly

� Negative finding:

� IFA: negative 

granulomatous vasculitis 

� ANCA- associated vasculitis

� Wegner

WG occurs at all ages and targets the respiratory tract and the kidneys

WG occur in adults. It does develop in children with a mean age at diagnosis of 14 yr.

There is a female predominance.

The diagnosis is confirmed by the presence of anti -PR3-specific ANCA and the finding of necrotizing granulomatous vasculitis on pulmonary- sinus or renal biopsy.    

Wegner

The ANCA test result is positive in 90% of children with WG.

� Positive finding:

� Fever

� Skin vasculitis

� Negative finding:

� C- ANCA&P-ANCA: NL

CCS

The presence of choronic asthma and pripheral eosinophilia suggested the diagnosis of CSS.

In 70% of cases of CSS mpo- ANCA are more common than PR3 ANCA.

Inflammatory disorder

� Crohn’s disease:

Choronic Inflammatory disorder of the bowel involves any region of the alimentary tract from the mouth to the anus.

Extra intestinal manifestation oral aphthous ulcers, pripheral arthritis, erythema nodosum digital clubing, episcleritis, renal stones and gall stones.

Inflammatory disorder

The diagnosis of Crohn depends on finding typical clinical features of disorder (history, physical exam, laboratory study and endoscopic or radiologic finding).

Crohn

� Positive finding:

� Skin lesion

� Negative finding:

� No history about GI problem

Sarcoidosis

This Is a rare multi system granulomatous disease of unknown etiology.

Children may present with non specific symptoms such as fever, weight loss and general malaise.

In older children pulmonary involvement is most frequent consist of dry, persistent cough.

Sarcoidosis

Extra thoracic lymphadenopathy and infiltration of the liver, spleen and bone marrow also occur often.

Cutaneous disease such as plaques nodules, erythema nodosume.

Other manifestation consists of ocular involvement, central nervous system, kidney disease, heart symptoms.

Sarcoidosis

Early onset Sarcoidosis in older children is triad uveitis, arthritis and rash.

Diagnosis requires characteristic non caseating granulomatous lesions in a biopsy specimen.  

Sarcoidosis

� Positive finding:

� Skin lesion

� Fever

� splenomegaly

� Negative finding:

� Skin biopsy

HLH

The diagnosis of HLH is established by full filing 1 or 2 of the following criteria:

� A molecular diagnosis consistent with HLH (PRF mutation, SAP mutation).

� Having 5 out of 8 of the following.

� Fever

� Splenomegaly

� Cytopenia (affecting >= 2 cell lineages, Hb<=9 (or <=10 for infants<=4 W of age), PLT<100000, NUT<1000)

HLH

�  TG>=265 and or hypofibrinogenemia<=150 mg/dl

�  Hemophagocytosis in the bone marrow, spleen or lymphnode with out evidence of malignancy

�  Low or absent NK cell cytotoxicity

�  Hyper ferritinemia>= 500

�  Elevated soluble CD 25

HLH

� Positive finding:

� Fever

� Anemia

� Thrombocytopenia

� Splenomegaly 

� Negative finding:

� Fibrinogen: NL

� BMA, BMB: NL

� CD 25: NL

� TG: NL

اقاي دكتر پيام سامعي

رزيدنت بيمارستان شهدا

به  نام خدا

شرح حال:

دختر 8 ساله  با تب از 40 روز قبل

عدم پاسخ به درمان آنتی بيوتيکی

(کليندامايسين، پنی سيلين،کوتريماکسازول،سفترياکسون، ونکومايسين)

شروع ضايعات پوستی از هفته دوم

اسپلنومگالی خفيف

IVIGپاسخ موقت تب به درمان کورتيکواستروييد و

ادامه وجود راشها و بازگشت تب

نکات مثبت پرونده:

تب

راش گرم ،  تندر، بدون خارش ، بدون پوسته ريزی

اسپلنومگالی خفیف

)ESR=140 خيلی بالا (ESR

واسکوليت لنفوسيتيک مزمن در بيوپسی

نکات مبهم پرونده:

  انجام شده؟PPD

اکوی قلب ؟

سابقه برخورد با حيوانات؟

الگوی تب؟

علل تب طول کشيده همراه راش:

عفونتها

بيماريهای روماتولوژيک (بافت همبند  و اتوايميون)

بيماريهای نئوپلاستيک

تب دارويی

تب ساختگی

عفونتها :

                           1- باکتريال

 الف: بروسلا   

+ : تب

+ : اسپلنومگالی

- : کشت خون منفی

  (باید تکرار شود)Grey Zone- : سرولوژی :

TB ب.

 ؟    PPD

سابقه تماس؟

 نرمالCXR

علائم تنفسی ندارد

ج . اندوکارديت

  اکوی قلب ؟

  - : کشت خون منفی

  - : عدم وجود تظاهرات بالینی نظیر:

Osler nodes ، splinter hemorrhages  ،Janeway lesions           

  - : بيمار بدحال نمی باشد

د. عفونتهای ریکتزيايی

  Mediterranean spotted fever

  (Rickettsia   conorrii)

برخورد با سگ ؟

 - : عدم لنفادنوپاتی 

Qه. تب

 (C. burnetii) عامل کوکسيلا بورنتی

انتقال : بيشتر از طريق آئروسل عفونی

+ : تب همراه آزمايشات نرمال

 کمتر از 20 (در 80% موارد)ESR - : معمولا

- : هيپرفيبرينوژنمی (در 67% موارد)

 مثبت (در 50% موارد)RF - :

2- عفونتهای ويرال:

) با سرولوژی رد شده.HIV  و HCV  و HBV(  

EBV   -

CMV   -   

3- قارچها

   - هیستوپلاسموزيس

 تب دارويی

معمولا 72 ساعت بعد از قطع دارو بهبود می يابد.

تب ساختگی

با بستری در بيمارستان و ثبت الگوی تب رد می شود

:اختلالات نئوپلاستيک

 نرمال، بيوپسی و آسپيراسيون مغز استخوان نرمال،LDH  نرمال، CBC

 نرمال : احتمال ضعيفCT  نرمال، Bone Scan   

اختلالات روماتولوژيک :

-  : علائم آرتريت  يا آرترالژی ندارد

-   : معاينه چشم نرمال است

-   : آزمايشات نرمال است

C3, C4, CH50, ANA, C-ANCA, P-ANCA, RF

Anti ds-DNA, Anti Cardiolipin, Anti Phosphlipid

   FEATURES THAT SUGGEST A VASCULITIC SYNDROME

CLINICAL FEATURES

�    Fever, weight loss, fatigue of unknown origin

 

�    Skin lesions (palpable purpura, vasculitic urticaria, livedo reticularis, nodules, ulcers)

 

�    Neurologic lesions (headache, mononeuritis multiplex, focal central nervous system lesions)

 

�    Arthralgia or arthritis, myalgia, or myositis
   Serositis

 

�    Hypertension

 

�    Pulmonary infiltrates or hemorrhage

 

LABORATORY FEATURES

�     Increased erythrocytes sedimentation rate or C-reactive protein level

 

�    Leukocytosis, anemia

 

�     Eosinophilia

 

�     Antineutrophil cytoplasmic antibodies

 

�     Elevated factor VIII–related antigen (von Willebrand factor)

 

�     Cryoglobulins

 

�     Circulating immune complexes

 

�     Hematuria, proteinuria, elevated serum creatinine

 

�  HEREDITARY PERIODIC FEVERS:

�  FMF (Familial Mediterranean Fever)

�  TRAPS ( TNF Recptor Associated Periodic Syndrom)

�  HIDS ( Hyper Immunoglobulinemia D Syndrom)

�  MWS (Muckle Wells Syndrom)

�  FCAS (Familial  Cold  Autoinflammatory Syndrom)

�  PFAPA (Periodic Fever ,Aphtous stomitis, Pharyngitis , and         cervical  Adenitis)

: FMF

بيماری نمی شود.

ممکن است از موتاسيونهای غیرشايع باشدبررسی ژنتيک باعث رد.

: TRAPS

بيوپسی پوست به نفع می باشد.

 خانم دكتر لاله محمدي

رزيدنت بيمارستان لقمان

IN THE NAME OF
 THE ABSOLUTE LIGHT

 

Problem List

 

1-Prolonged Fever

2-Skin Lesion

3-Skin Biopsy:Chronic Lymphocytic Vasculitis

4-Anemia,Trombocythopenia,Elevated ESR & CRP

5-Mild Splenomegaly

6-chills

Erythema  Nodosum

Streptococcus Pharyngitis

EBV

Sarcoidosis

TB

Hodgkin lymphoma

HIV

Histoplasmosis

Cat Scratch Disease

leptospirosis

Yersinosis

FUO

1-Generalized :

TB

Sarcoidosis

Cat Scratch Disease

Leptospirosis

Malaria

Salmonellosis

Yersinia

Tularemia

HIV

Trench Fever

Brucellosis

2-localized Infection:

Bone & Joint

Infective Endocarditis

Intra Abdominal Abscess

Hepatic Infection

Upper Respiratory Tract Infection

UTI

3-Connective Tissue:

Vasculitis

4-Neoplasm:  

Lukemia

lymphoma

 

5-Other Causes:

Periodic Fever:

1- FMF

2-TRAPS

3-HILLS

4-Cyclic Neutropenia

IBD

Immune Deficiency

Fctitious Fever

Drug Fever

Definitive DDX

TRAPS

FMF

EBV

SLE

THANKS FOR YOUR ATTENTION

 دكتر عبدالله كريمي

فوق تخصص عفوني اطفال

دكتر محبوبه منصوري

فوق تخصص الرژي و ايمونولوژي

دكتر تقي ارزانيان

فوق تخصص خون اطفال