Vasculitis in children II

Ali telfah Noura Khalid

Abdullah Al-Shorman

Vasculitis in children

Definition of vasculitis is an inflammatory destructive process affecting arteries and veins or

including infiltration of the vessel wall by inflammatory cells without destruction.

Site of vasculitis either skin only like cutanous vasculitis or internal organ only like isolated angiitis of

the CNS or both skin and internal organ like systemic vasculitis.It also depends on size of vessel involved

either small (Arterioles, Venules, Capillaries), medium (Main visceral arterioles + branches) or large

(Aorta and largest branches) and the lesion may be focal causing aneurysms or segmental causing

stenosis or occlusion .

Pathogeneses:

-There is No single mechanism explain all vasculitidies.

-there are abnormalities noted in various vasculitides :

1-Polymorphs - Endothelial cells

2-Lymphocytes - Humoral immunity

3-Platelets

There are three major Mechanisms suggested:

1-Immune complex chemoattractant hypothesis(I.C.)

2-Adhesion molecular (A.M.)

3-Antibody mediated vascular injury

Vasculitis in children :

Large vessel vasculitis

1-Giant cell (temporal arteritis)

Granulomatous arteritis of the aorta and its major branches with a predilection for the extracranial

branches of the carotid artery. Often involved in the temporal artery. May seen in children but Usually

occurs in patients older than 50 years & often associated with polymyalgia rheumatica.

2-Takayasu arteritis

Granulomatous inflammation of the aorta and its major branches. Usually occurs in patients younger

than 50.

Medium size vessel vasculitis

Polyarteritis nodosa

1- Necrotizing inflammation of medium-sized or small arteries without glowmrulonephritis or vasculitis in arterioles, capillaries or venules.

2- Kawasaki disease Arteries involving large, medium-sized and small arteries and associated with mucocutaneous

lymph node syndrome. Coronary artery are often involved. Aorta and veins may be involved. Usually

occurs in children.

Small vessel vasculitis

1- Wenegers granulomatous Granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small to

medium-sized vessels (e.g. capillaries, venules, arterioles, and arteries). Necrotizing glomerulonephritis

is common.

2- Churg-Strauss syndrome

Eosinophil-rich and granulomatous inflammation involving the respiratory tract, and necrotizing

vasculitis affecting small to medium-sized vessels, and associated with asthma and eosinophilia.

3- Microscopic polyangitis

Necrotizing vasculitis, with few or no immune deposits, affecting small vessels (I.e. capillaries, venules,

or arterioles). Necrotizing arteritis involving small and medium-sized arteries may be present.

Necrotizing glomerulonephritis is very common. Pulmonary capillaries often occurs.

4-Henoch-Schonlein purpura

Vasculitis wth IgA-dominant immune deposits, affecting small vessels (I.e. capillaries, venules, or

arterioles). Typically involves skin, gut and glomeruli, and is associated with arthralgias or arthritis.

5-Essential cryoglobulinemic vasculitis

Vasculitis with cryoglobulin immune deposits, affecting small vessel (I.e. capillaries, venules,

orarterioles), and associated with cryoglobulins in serum. Skin and glomeruli are often involved.

6-Cutaneous leukocytoclastic angiitis

Isolated cutaneous leukocytoclastic angiitis without systemic vasculitis or glomerulonephritis

Common Presentations of the Vasculitic Syndromes :

Syndrome Presentation

Constitutional Fever, weight loss, weakness, fatigue

Musculoskeletal Arthralgia, myalgia, arthritis

Cutaneous Palpable purpura, nodules, urticaria, livedo reticularis, superficial phlebitis, ischemic

lesions

Neurologic Headache, stroke, mononeuritis multiplex

Syndrome Presentation

Head and neck Sinusitis, chondritis,otitis, iritis

Renal Nephritis, infarction, hypertension

Pulmonary Hemorrhage, cavities, nodules, infiltrates

Laboratory Anemia, elevated ESR, abnormal liver function tests, hematuria

Laboratory studies in Vasculitis

A. Nonspecific

- Complete blood count

- Erythrocyte sedimentation rate (ESR)

- C-reactive protein

B. Organ involvement

- Creatinine

- Urinalysis Liver enzymes

- Electrocardiogram - Echocardiogram

- Creatinine phosphokinase

- Chest roentgenogram

- Sinus roentgenograms

- Electromyography/nerve conduction studies

C. Angiography

D. Biopsy

C. ANGIOGRAPHY:

- Large and medium vessels vasculitis

- Do selected angiogram according to clinical findings

- there is False positive results in:

- Drug induced vasospasm

- Fibromuscular dysplesia

- Look for narrowing, obstruction or aneurysmal dilatation

D. Biopsy:

- Avoid blind biopsy

- Lesions may be segmental

- Skin changes do it prove systemic or visceral involvement

- Pathological findings must be interpreted with clinical picture.

General Approach to Diagnosis or DDx:

1- Suspect the diagnosis. 2- Exclude other processes. 3- Determine the organs and vessels involved.

4- Attempt to reach specific type of vasculitis on basis of clinical features and helpful laboratory

tests.

Conditions that may mimic systemic vasculitis.

- Drug exposure Coccaine

Amphethamine

Penicillins, supha drugs

Anticonvulsants Hydralazine, Propylthiouracil

- Infections - Malignant disease - Atrial myxoma - Cholesterol emboli - Antiphospholipid antibody syndrome - Other connective tissue disorders

Infection-related vasculitis

May be Viral like : HIV , Hepatitis B,C ,EBV, herpes zoster ,Parvovirus B19 and CMV

-Bacterial/fungal: sub-acute bacterial endocarditis (SBE)

- Mycobacterial:Tuberculosis

-Spirochetal : Syphilis

-Rickettsial: Rocky Mountain spotted fever

Now we will move to vasculitis syndrome which is important in children

First of all Kawasaki syndrome:

Is A self-limited vasculitis of unknown etiology first they said its of known etiology but the known

etiology is for vasculitis. Kawasaki predominantly affects children younger than 5 years. It is now the

most common cause of acquired heart disease in children in the United States and Japan.

Kawasaki disease is Idiopathic multisystem disease characterized by vasculitis of small & medium blood

vessels, including coronary arteries

Epidemiology

-Median age of affected children = 2.3 years

-80% of cases in children < 4 yrs, 5% of cases in children > 10 yrs

-Males:females = 1.5-1.7:1

-Recurs in 3%

-Positive family history in 1% but 13% risk of occurrence in twins

-Overall U.S. in-hospital mortality 0.17%

-Annual incidence of 4-15/100,000 children under 5 years of age

-Over-represented in Asian-Americans, African-Americans next most prevalent

-Seasonal variation

-More cases in winter and spring but occurs throughout the year

Diagnostic Criteria for Kawasaki disease :

-Fever for at least 5 days

-At least 4 of the following 5 features:

1- Changes in the extremities ,Edema, erythema, desquamation

2- Polymorphous exanthem, usually truncal

3- Conjunctival injection

4- Erythema&/or fissuring of lips and oral cavity

5- Cervical lymphadenopathy

-Or the Illness not explained by other known disease process

So the diagnosis of Kawasaki disease is a diagnosis of exclusion and the must follow the previous order

meaning that we must have fever for 5 days then 4 of 5 criteria at last he must be not diagnosed by

other disease .

Atypical or Incomplete Kawasaki Disease:

-Present with < 4 of 5 diagnostic criteria

-Compatible laboratory findings

-Still develop coronary artery aneurysms

-No other explanation for the illness

-More common in children < 1 year of age

-2004 AHA guidelines offer new evaluation and treatment algorithm

Differential Diagnosis for Kawasaki disease:

Infectious (manly viral)

- Manly Measles (maculopapular rash and redness of conjunctiva with fever ) then Group A beta-hemolytic strep (causing scarlet fever) can closely resemble KD

- Bacterial: severe staph infections w/toxin release - Viral: adenovirus, enterovirus, EBV, roseola

- Spirocheteal: Lyme disease, Leptospirosis - Parasitic: Toxoplasmosis - Rickettsial: Rocky Mountain spotted fever, Typhus

Immunological/Allergic

- Juvenile rheumatoid arthritis(JRA) we talked about it in rheumatic fever and Kawasaki disease. there are three types of JRA here we are concerned about the systemic one

which has maculopapular rash, hepatosplenomegaly and fever

- Atypical acute rheumatic fever ( ARF) - Hypersensitivity reactions - Stevens-Johnson syndrome which is erythema multiforme with involvement of the oral

cavity

Toxins

- Mercury

Phases of Disease:

Acute (1-2 weeks from onset)

- Febrile, irritable, toxic appearing

- Oral changes, rash, edema/erythema of feet and cervical lymphadenopathy .

Subacute (2-8 weeks from onset)

- Desquamation of skin , may have persistent arthritis or arthralgias

- Gradual improvement even without treatment

Convalescent (Months to years later)

This is conjunctival redness which is seen in measles and Kawasaki disease

This is a strawberry tongue with fissuring of the lips

Maculopapular rash with edema of the hands Maculopapular rash of the trunk

This is the desquamation of the skin

This is like erythema multiforme

Lymphadenopathy

Other symptoms and signs of Kawasaki disease :

1- Respiratory

- Rhinorrhea, cough, pulmonary infiltrate

2- GI

- Diarrhea, vomiting, abdominal pain, hydrops of the gallbladder, jaundice

3- Neurologic

- Irritability, aseptic meningitis, facial palsy, hearing loss

4- Musculoskeletal

- Myositis, arthralgia, arthritis

This Is hydrops of the gallbladder

Kawasaki Disease: Lab results

in the acute stage there is

- Leukocytosis

- Left shift

- Mild anemia

- Thrombocytopenia/ Thrombocytosis

- Elevated ESR

- Elevated CRP

- Hypoalbuminemia

- Elevated transaminases (liver enzymes )

- Sterile pyuria

And in the late stage there is :

- Thrombocytosis

- Elevated CRP

Cardiovascular Manifestations of Acute Kawasaki Disease

EKG changes

- Arrhythmias

- Abnormal Q waves

- Prolonged PR and/or QT intervals

- Low voltage

- ST-Twave changes.

CXR cardiomegaly

( Some pt. with Kawasaki disease may have none of the cardiovascular problems)

The DR. said exactly (Cardiovascular Manifestations of Acute Kawasaki Disease can be none of cases of

acute Kawasaki have abnormalities In the heart ) so that is my interpretation of this sentence !!

Suggestive of myocarditis (50%)

- Tachycardia, murmur, gallop rhythms

- Disproportionate to degree of fever & anemia

- Suggestive of pericarditis

- Present in 25% although symptoms are rare

- Distant heart tones, pericardial friction rub, tamponade

Echocardiographic Findings:

- Myocarditis with dysfunction

- Pericarditis with an effusion

-Valvar insufficiency

- Coronary arterial changes

Coronary Arterial Changes

- 15% to 25 % of untreated patients develop coronary artery changes

- 3-7% if untreated in first 10 days of fever with IVIG

- Most commonly proximal, can be distal

*Left main > Right

Coronary Aneurysms

Size:

- Small =

Coronary Aneurysm History:

- 50 % regress to normal by echocardiogram

- 25 % become smaller

- 25 % do not regress

- 7-20 % develop stenosis or myocardial infarction attributed to their aneurysms

- Approximately 50% of aneurysms resolve if they are :

* Smaller size

* Fusiform morphology

* Female gender

* Age less than 1 year

- Giant aneurysms (>8mm) have worst prognosis

Cardiovascular Sequelae:

- 0.3-2% mortality rate due to cardiac disease

* 10% from early myocarditis

- Aneurysms may thrombose, cause MI/death

- MI is principal cause of death in KD

- 32% mortality

- Most often in the first year

- Majority while at rest/sleeping

- About 1/3 asymptomatic

Acute Kawasaki Disease: Treatment:

1- IVIG: 2g/kg as one-time dose

- Beneficial effect 1st reported by Japanese - Mechanism of action is unclear - Significant reduction in CAA in pts treated with IVIG plus aspirin vs. aspirin alone

(15-25%-3-5%)

- Efficacy unclear after day 10 of illness *We must give IVIG when we diagnose Kawasaki disorder

- 70-90% defervesce & show symptom resolution within 2-3 days of treatment

-

to a second course

2- Aspirin

- High dose (80-100 mg/kg/day) until afebrile x 48 hrs &/or decrease in acute phase reactants

- Need high doses in acute phase due to malabsorption of ASA

- Dosage of ASA in acute phase does not seem to affect subsequent incidence of CAA

So the aspirin is for acute febrile illness not for CAA

-Decrease aspirin in the second stage after 2-3 weeks to low dose (3-5 mg/kg/day) for 6-8 weeks or until

platelet levels normalize ( because there is thrombocytosis

-No evidence of effect on CAA when used alone

-Due to potential risk of Reye syndrome ( hepatoencephalopathy caused by influenza or varicella

infections while using aspirin) instruct parents about symptoms of influenza or varicella

3- Aggressive support with diuretics & inotropes for some patients with myocarditis

4- Antibiotics while excluding bacterial infection like toxic shock syndrome

5- Conflicting data about steroids

- Reports of higher incidence of aneurysms & more ischemic heart dz in pts w/aneurysms

- Case report of KD refractory to IVIG but responsive to high-dose steroids & cyclosporine A

- Ongoing NHLBI multicenter randomized placebo-blind trial in progress

HenochSchnlein Purpura

Also called anaphylactoid purpura, a systemic vasculitis manifested with:

1. Palpable Purpura

2. Arthralgia

3. GI involvement

4. Glomerulonephritis

Epidemiology

- 90% of cases are reported in children

- Peak incidence is between 4-7 years

- M : F = 1.5 : 1

- 50% follow upper respiratory tract infection

- Renal disease is more severe in adults than in children

Etiology

- The likely mechanism is thought to be an immune complex mediated disease with deposits of

glomerular capillaries, dermal capillaries, and GI tract. The mesangial deposits of IgA are the same seen

in IgA nephropathy

- Precipitating Antigens:

URTI (70% of cases) Measles Rubella

Parvovirus Mycoplasma Kawasaki

Toxocara Ameobiasis Salmonellosis

Clostridium Difficile H. Pyluri Adenovirus

Legionella Tuberculosis Mumps

Etc...

- Drugs also may precipitate antigens like Vancomycin, Streptokinase, Ranitidine

- Food hypersensitivity, cold exposure, autosomal recessive, chronic granulomatous disease,

myelodysplastic syndrome, small cell lung disease, and breast cancer can also lead to HSP

Dermatological Findings

There is a leukocytoclastic vasculitis with IgA deposition, so if we take a biopsy from the skin we will see

leukocytoclastic vasculitis with IgA deposition in the skin and in the glomeruli

Renal Findings

- Granular deposits of IgA

- Mesangio-Proliferative Glomerulonephritis

- Crescent formation

Clinical features

1. Palpable Purpura:

mainly seen in the gravity areas like lower limbs, buttocks, dorsum of foot (in infancy we can see it also

on the face, ears, hands) however, can also be seen in the trunk and arms, we might also find swelling of

joints with a purpuric rash.

* There is no diagnosis of HenochSchnlein purpura without the palpable purpura ! So if the patient

complains of abdominal pain, renal disease, and arthralgia we can't diagnose him as HSP without the

presence of purpural skin rash.

Lesions start as erythematous macules that progress to purpuric non-blanching. This is the difference

between HSP and ITP; in HSP you see and feel the purpura above the skin so it is a palpable purpura, but

in ITP there is a bleeding under the skin that causes visible purpura and ecchymosis but we can't feel

them.

2. Arthralgia:

more common in adults and mostly affecting knees and ankles but generally self-limiting.

3. GI Involvement:

is more common in children, symptoms include abdominal pain, nausea, diarrhea, constipation, bowel

intussusception -this is the most important one because the patient presents with abdominal pain and

possibly GI bleeding and you could forget about intussusception. Although in the pathogenesis of HSP

we find edema and purpuric skin lesions and purpuric manifestations in the mucosa of the intestinethe

leading area for intussusception!

We might suspect HSP and GI bleeding hence this is a surgical case that needs to be treated surgically

while HSP is a medical case that can be treated by observation medications.

4. Renal Involvement:

up to 50% of patients usually more rapidly progressive glomerulonephritis in others.

it is rare in children. It may present with hematuria or have mild glomerulonephritis leading to

microscopic hematuria that can lead to rapidly progressive glomerulonephritis with RBC cast; and of

course the most common presentation of glomerulonephritis is the finding of RBS cast along with other

manifestations like volume overload, hypertension and encephalopathy.

the renal involvement usually resolves spontaneously if there is mild glomerulonephritis.

Diagnostic evaluation

may have mild leukocytosis, normal platelets count, normal serum complement levels.

-Post-Streptococcal Glomerulonephritis has decreased levels of serum C3.

-Decreased platelets count suggests ITP.

-Elevated IgA can be in 50% of cases because this is a deposition of IgA resembling IgA nephropathy.

Clinical Diagnosis

- Skin biopy can be helpful to use to confirm IgA and C3 deposits and leukocytic clasts

- Renal biopsy which isnt usually needed for diagnosis may show mesangial IgA deposits and

segmental glomerulonephritis.

Management

- Usually self-limiting (1-6) weeks

- Steroids may decrease tissue edema so we use them ONLY in 2 conditions:

1. GI bleeding with severe abdominal pain

2.CNS bleeding

Otherwise we cannot use steroids for treatment of other symptoms like skin or kidney manifestations,

because use of steroids does not lessen the chance of recurrence nor shorten the duration of the

disease's course, and it hasn't shown to be beneficial for renal diseases or dermal manifestations

- If rapidly-progressive glomerulonephritis, multi-drug regimens with cytotoxic drugs however not

may report in treatment of adults so we can use plasmapheresis and IV-Ig as a symptomatic

management of the GI symptoms and surgical intervention if there is an intussusception.

Prognostic Factors for HSP

- Generally, a milder course in children with a shorter duration and a fewer recurrence.

- Proteinuria of more than 1 mg/day have worse prognosis and develop nephrotic syndrome.

- 1-5% of children progress to end-stage renal failure.

- Recurrence is up to 40% of patients within 1-6 week.

The End Done by :

Ali telfah

Noura Khalid