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Polyarteritis nodosa in childhood.

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POLYARTERITIS NODOSA IN CHILDHOOD
A Clinical Pathologic Study
ROBERT E. ETTLINGER, AUDREY M. NELSON, EDMUND C. BURKE, and J. T. LIE
The clinical and pathologic findings of 2 infants
and 7 older children with polyarteritis nadosa who were
autopsied are reported. The most frequent clinical features included prolonged high fever, skin rash, abdominal symptoms, leukocytosis, proteinuria, and signs of either cardiac or renal failure. The 2 infants died of
cardiac arrest, whereas renal or neurologic involyement
was the most common cause of death in the older children. A consistent finding at autopsy was arteritis of the
epicardial coronary arteries.
Polyarteritis nodosa (PAN) is a form of necrotizing vasculitis which occurs in children as well as adults.
The disease varies in its presentation from a relatively
benign cutaneous form which may resolve without
treatment to a severe disseminated form which is usually fatal. In children the disseminated form may be divided into the subtypes of infantile polyarteritis nodosa
(IPN) and childhood polyarteritis nodosa (CPN). The
infantile form appears to have a predilection for the coronary arteries, whereas the childhood form is similar to
PAN in adults. Recently, another variant of the disease
has been described under the term mucocutaneous
lymph node syndrome (MCLS) or Kawasaki's disease.
Only 1 to 2% of the patients with mucocutaneous lymph
From the Divisions of Rheumatology and Internal Medicine,
Pediatrics and Pathology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota.
Robert E. Ettlinger, MD: Instructor in Medicine; Audrey M.
Nelson, MD: Assistant Professor of Medicine; Edmund C. Burke,
M D Professor of Pediatrics; J. T. Lie, MD: Professor of Pathology.
Address reprint requests to Audrey M. Nelson, MD, Mayo
Clinic, Rochester, MN 55901.
Submitted for publication December 5, 1977; accepted in revised form April 10. 1979.
Arthritis and Rheumatism, Vol. 22, No.8 (August 1979)
node syndrome die, but those who do, have pathologic
features virtually identical with those previously described in infantile polyarteritis nodosa (1-3).
Establishing the diagnosis of polyarteritis nodosa
in childhood remains a difficult task despite excellent
clinical descriptions of this illness in children as early as
1908 (4). Keith and Baggenstoss ( 5 ) estimated that the
diagnosis was made prior to death in only 15% of 44
cases reviewed through 1941. Among 20 infants less
than 2 years of age reported in 1963, Roberts and Fetterman (6) found that PAN was considered in only 2
cases prior to autopsy. Only 26 cases in infancy were reported through 1973 (7) and less than 150 cases in older
children were identified by Reimold et a1 (8) through
1976.
Recent reports that angiograms in children have
revealed aneurysms typical of polyarteritis nodosa provide the hope that such studies will allow the diagnosis
of this disease to be made more readily (9,lO). However,
the use of such invasive procedures in very ill young patients who may have cardiac failure has an attendant
risk and must be guided by the strong clinical suspicion
that such aneurysms will be found. In an attempt to define a more consistently identifiable clinical picture of
this condition in children, we reviewed all the cases of
autopsy-proven childhood polyarteritis nodosa seen at
the Mayo Clinic.
MATERIALS AND METHODS
All the reports from 1937 to 1977 of children aged 16
years or younger whose h a 1 diagnosis included polyarteritis
nodosa or systemic vasculitis were reviewed. Only cases in
which the diagnosis was confirmed at autopsy were included.
The autopsy material was independently reviewed in detail by
PAN IN CHILDHOOD
82 1
Table 1. Clinical features of children with polyarteritis nodosa
~~
Duration of illness
Case no.
Age at
onset, sex
Pre-hosp
2 mo, F
5 mo, M
10 days
Cause of death
In hosp
Premortem
diagnosis
Total
Cardiac
Uremia
Other
Infants
1
2
Older children
3
4
5
6
I
8
9
Days
3 yr, F
5 mo
5 yr, M
4 wk
9 yr, F
10 yr, M
11 yr, F
12 yr, M
14 yr, M
5 wk
1 wk
6 wk
5 mo
2 wk
4 hr
18 days
5 days
2 wk
Hours
5 wk
4 wk
2 days
3 wk
Days
1 mo
No
5 mo
No
No
No
No
YeS
YeS
6 wk
5 wk
6 wk
10 wk
5 mo
I5 mo
two pathologists. Nine cases were identilied in which the pathologists agreed that PAN was present, according to the histopathologic criteria of Arkin (1 l). These cases form the population presented in this study. Three of the cases have
previously been reported (5,7).
RESULTS
Po'yarteritis
of age
in
less than year
Clinical features. Only 2 of our patients were less
than 1 year old at the onset of disease (patients 1 and 2,
Tables 1 4 ) . The duration of illness was .less than 1
month in both patients and in neither was the diagnosis
X
X
No
Colonic perforation
X
X
Status epilepticus
X
Cerebral edema
No
X
suspected before death. Death was attributed to cardiac
in both cases. The clinical presentations in
the 2 infants (Table 2) seemed to be quite different, although few details were available for patient 1 who had
acute and intractable congestive heart failure. Patient 2
was considered to have an acute febrile upper respiratory infection with prominent mucocutaneous features.
Despite treatment with salicylates and antibiotics, congestive heart failure and aseptic meningitis progressively dominated the clinical course of patient 2 until
sudden death occurred.
Laboratory features. Laboratory features were
available only for patient 2 (Table 3). Leukocytosis and
Table 2. Clinical symptoms and signs in children with polyarteritis nodosa
Older children.
InfMtS*
Symptoms
Fever > 39OC for 2 5 days
Rash
Abdominal pain
Vomiting
Cardiomegaly
Resting tachycardia
Hypertension ( 2 1 50/ LOO)
Erythematous oral mucosa
Strawberry tongue
Dryness, erythema of lips
Indurated edema of extremities
Cervical lymphadenopathy
Arthritis
Aseptic meningitis
Seizures
cough
Splenomegaly
Peripheral neuropathy
Pencarditis
Patient numbers.
ND = Not determined.
I
+
ND
+
+
2
3
4
5
6
I
8
9
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
ND
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
ETTLINGER ET AL
822
Table 3. Laboratory features of children with polyarteritisnodosa
Infantst
Laboratory findings*
I
Leukocytosis (> 15,000)
Proteinuria 2 +2
Pyuria 2 +2
Hematuria 2 +2
ESR > 50 mm/hr
Azotemia
CSF pleocytosis
A S 0 titer > 400 Todd units
Platelets > 400,OOO
ST-T A’s on EKG
Other
0
0
0
0
0
0
0
0
0
0
Older children?
2
3
4
5
6
7
8
+
+
+
+
+
+
+
+
+
+
+
+
+
0
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
0
0
0
0
0
0
0
-
+
+
1Total
0
0
0
0
-
+
*
9
0
0
0
T SCOT +Cryoglobulins
complement
fSGOT
+
= present; - = absent;0 = not done.
f Patient numbers.
an elevated sedimentation rate were present, and on
three occasions spinal fluid pleocytosis was observed.
The chest x-ray showed progressive cardiac enlargement and an electrocardiogram revealed nonspecific ST
segment and T wave changes.
Autopsy findings. As in the older group of children, the pathologic findings (Table 4) included arteritis
of the epicardial coronary arteries. The involvement of
other organs was more limited in the infants. In patient
1 arteritis was confined to the heart where an acute
myocardial infarction had occurred. In patient 2 arteritis was present in the testes, adrenal glands, aorta, and
temporal, pulmonary, and iliac arteries, but the most
impressive pathologic findings were aneurysms, thromboses, and arteritis of the coronary vessels.
Polyarteritis nodosa in older children
Clinical features. These 7 children ranged in age
from 3 to 15 years at the onset of illness with a median
age of 10 years (patients 3-9, Tables 1-4). Neither males
nor females predominated. The total duration of illness
ranged from 5 weeks to 15 months with a median duration of 10 weeks.
Unlike the infant patients, the older children
rarely died of cardiac involvement. In only 1 older patient (patient 4) was cardiac arrest the terminal event,
and this took place during anesthesia for an open renal
biopsy amid the acidosis and electrolyte imbalance associated with renal failure. Uremia was more clearly the
cause of death in 3 other patients (patients 5, 7, and 9),
whereas central nervous system involvement- led to
death in patients 6 (status epilepticus) and 8 (cerebral
edema). Patient 3 died of sepsis from a colonic perforation.
The clinical features most commonly shared by
this group of patients (Table 2) were fever unresponsive
to antibiotic therapy, signs of cardiac failure (cardiomegaly, cough, hepatomegaly, and resting tachycardia), and abdominal complaints (severe diffuse
pain, nausea, and vomiting). Skin rashes were common
and usually consisted of a diffuse maculopapular eruption on both the trunk and extremities. However, occasionally the rashes were purpuric or petechial in character. Mucocutaneous features other than rash were
frequent and included mucosal erythema, dryness, and
fissuring of the lips and prominence of the lingual papillae (“strawberry tongue”). Indurated edema of the
extremities was also observed in some of the patients.
Arthralgia was present in 4 patients and in 3 of these a
frank mono- or oligoarthritis was noted. Patient 3 had
an elbow monarthritis, patient 6 had bilateral knee effusions, and patient 8 had symmetrical ankle synovitis.
In this series, corticosteroids were administered
to only 1 child (patient 6) and his clinical course seemed
unaltered. Except for patient 9 who experienced a spontaneous relative remission of 12 months until progressive uremia developed, all children had a steady downhill course. In only 2 cases (patients 7 and 8) was the
diagnosis suspected prior to autopsy.
Laboratory features. Leukocytosis over 15,000
cells/mm’ was present in all but 1 patient (Table 3).
Proteinuria of at least +2 was seen in all but 1 case as
well. Urinary sediment abnormalities were less frequent
and quite varied but mostly consisted of moderate mi-
PAN IN CHILDHOOD
823
Table 4. Pathologic findings in children with polyarteritis nodosa
Infants.
1
Heart
Acute infarction
Myocarditis
Myocardial fibrosis
Marked cardiomegaly
Pericarditis
Endocarditis
Epicardial coronary arteritis
Arteritis of the:
Adrenal glands
Kidney
Liver
Lung
Gallbladder
Testes
Striated muscle
Urinary bladder
Pancreas
Mesentary
Skin
Peripheral nerve
Aorta, iliac, pulmonary,
and temporal arteries
~~
+
+
Older children*
2
3
4
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
5
+
+
+
+
+
+
+
6
+
+
+
+
+
+
+
+
+
+
+
7
8
+
+
+
+
+
+
9
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
~
* Patient number.
croscopic hematuria often accompanied by mild pyuria.
Casts were rarely observed. Electrocardiographic abnormalities such as ST segment changes and T wave inversion were present in the 3 patients on whom recordings were obtained. The erythrocyte sedimentation rate
was elevated markedly (over 80 mm/hour) in 3 patients
and over 30 mm/hour in all 6 patients who had this test
performed. Hepatitis B antigen was absent in the one
child in whom it was sought.
Autopsy findings. Arteritis of the epicardial coronary arteries was present in every patient (Table 4). One
patient (patient 8) had suffered an acute myocardial infarction. Cardiomegaly, diffuse myocarditis, or myocardial fibrosis was present in every case. Unlike the
findings in the 2 infant patients, the distribution of vasculitis in this group of older children was more widespread and included the adrenal glands, kidneys, and
liver in the majority of cases.
DISCUSSION
Since 1959 when Munro-Faure published her excellent review of polyarteritis nodosa in infancy (12), it
has been customary to consider childhood PAN to be
composed of two entities: infantile PAN (IPN) and
PAN of older children which is indistinguishable from
that in adults (CPN). Pathologically defined IPN ap-
pears to occur only in children less than 24 months of
age (1). In IPN the epicardial and/or intramural coronary arteries are involved either alone or with a limited
number of other arteries and organs, whereas the distribution for CPN is more widespread, yet may spare the
heart (1,12,13). In addition to the difference in the age
of children affected by IPN and CPN, clinical differences also exist between these entities. Children with
IPN have a shorter duration of illness, fewer nephritic
features, and a morbilliform, rather than a petechial or
purpuric, rash (1,13). Although our series included only
2 infants with infantile polyarteritis nodosa, these children had the most rapidly progressive courses as well as
the most restricted distribution of arteritis. Hypertension and seizures occur more commonly among
older children with this condition (8,13). Painful subcutaneous arteritic nodules, seen frequently in a recent series of older children (14), were not observed in our patients and only rarely have been reported previously (5).
The mucocutaneous lymph node syndrome
(MCLS)was first described in the English literature in
1974 (15). It is an acute febrile disease of children, usually less than 5 years of age, characterized by edema,
erythema, and desquamation of the peripheral extremities, congestion and erythema of mucosal surfaces,
a polymorphous rash, and lymphadenopathy. Although
824
in the majority of cases the illness runs a benign, selflimited course of 2 to 3 weeks (16), a small but disturbingly constant 1 to 2% of children with this syndrome
die, often suddenly and unexpectedly, at a time when
they appear to be recovering (17).
Autopsy studies of children who died of mucocutaneous lymph node syndrome have revealed that arteritis is present in virtually every case with a peculiar predisposition for the epicardial coronary arteries (2,3).
Numerous investigators have noted that the arteritis of
MCLS is both macroscopically and microscopically
identical to that seen in infantile polyarteritis nodosa
(1-3,15,17,18). Even among survivors of MCLS, coronary angiography has revealed coronary artery aneurysms (19-21) like those commonly seen in IPN
(6,9,10,22).
Despite the variability in the presenting clinical
manifestations among our group of fatally ill children, a
consistent clinical picture emerges. The most common
features were high and prolonged fever, skin rash, abdominal pain, diarrhea or vomiting, leukocytosis, proteinuria, and signs of either cardiac or renal failure. All
but 1 of the patients had five of these six findings. Hypertension and aseptic meningitis occasionally complicated this basic pattern. Mucous membrane lesions,
lymphadenopathy, and arthritis were observed less
commonly. In most cases (patients 2, 4-8) a history of
preceding upper respiratory infection with pharyngitis
was obtained.
Infection was the diagnosis first considered in
most cases and this was aggressively pursued despite
negative culture results and lack of response to broad
spectrum antibiotics. When renal involvement commenced, the diagnosis often shifted to poststreptococcal
glomerulonephritis, Henoch-Schonlein purpura, or
idiopathic glomerulonephritis. Cardiac decompensation
was usually attributed to concurrent uremia or rheumatic fever.
Some of the infants as well as older children in
this series had findings similar to those seen in mucocutaneous lymph node syndrome such as fever, rash, mucosal erythema, strawberry tongue, and lymphadenopathy. However, none of them had the bulbar conjunctival
injection nor the desquamation of the fingertips so typical of this syndrome (2,15,23). In this respect, our series
of cases resembles that of Fink (13). In contrast, among
a series of cases of IPN, CPN, and MCLS, Landing and
Larson ( 1) found numerous mucocutaneous features
only within the MCLS/IPN group, supporting a close
relationship between the two conditions. Another fea-
ETTLINGER ET AL
ture of MCLS, indurated edema of the extremities, occurred in several children in our series. However, much
of this edema may have resulted from the anasarca of
terminal renal or cardiac failure rather than representing the transient woody swelling of MCLS (16). Three
of the 4 children in our series who had platelet counts
determined had thrombocytosis which occurs in MCLS
(23). Thus, although some clinical features in our series
of cases of polyarteritis nodosa in children are suggestive of MCLS, this retrospective review does not allow
us to adequately test the hypothesis that childhood
polyarteritis nodosa or infantile polyarteritis nodosa
and mucocutaneous lymph node syndrome are all the
same disease.
Since PAN in children is such a serious and often rapidly fatal disease, early recognition and treatment are necessary. When a child is seen with an acute,
progressive illness, biopsies of clinically suspicious areas
or visceral or coronary angiography should be considered when infection has been excluded and when the
following six features are present: a high fever lasting
more than 5 days; rash; abdominal symptoms of pain,
vomiting, or diarrhea; leukocytosis of over 15,000 cells/
mm3;proteinuria of over +2; and clinical signs of either
cardiac or renal failure. If the clinical criteria for MCLS
are met as well (3), a more conservative diagnostic approach may be followed unless symptoms or signs of
major organ failure are present or the syndrome persists
for longer than 2 weeks. Serial tests of renal and cardiac
function may help select the appropriate candidates for
angiography as has been suggested by other workers
(17,2 1). This approach may serve to identify those children with CPN as well as those with IPN who may
mimic MCLS. It is important to separate the patients
with MCLS because this illness seems to be most appropriately treated with salicylates (23). In contrast, some
children with CPN (8,24,25) and IPN (9,lO) have responded to corticosteroid and immunosuppressive therapy, so the prompt recognition of these illnesses may
well be life-saving.
ACKNOWLEDGMENT
We acknowledge the aid of Dr. S. I. Gutman who participated in the review of the autopsy material from these patients.
REFERENCES
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with coronary artery involvement and fatal mucocutaneous lymph node syndrome the same? Comparison of
PAN IN CHILDHOOD
20 patients from North America with patients from Hawaii and Japan. Pediatrics 59:65 1-662, 1977
2. Tanaka N: Kawasaki disease (acute febrile infantile
muco-cutaneous lymph node syndrome) in Japan: relationship with infantile periarteritis nodosa. Pathol Microbiol (Basel) 43:204-218, 1975
3. Tanaka N, Sekimoto K, Naoe S: Kawasaki disease: relationship with infantile periarteritis nodosa. Arch Pathol
Lab Med 100:81-86,1976
4. Dickson WEC: Polyarteritis acuta nodosa and periarteritis nodosa. J Pathol Bacteriol 12:31-57, 1908
5. Keith HM, Baggenstoss AH: Primary arteritis (periarteritis nodosa) among children. J Pediatr 18:494-506,
1941
6. Roberts FB, Fetterman GH: Polyarteritis nodosa in infancy. J Pediatr 63519-529, 1963
7. Gillespie DN, Burke EC, Holley KE: Polyarteritis nodosa
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8. Reimold EW, Weinberg AG, Fink CW, Battles ND: Polyarteritis in children. Am J Dis Child 130:534-541, 1976
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NS: Regression of coronary-artery aneurysms in infantile
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I977
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825
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18. Yanagisawa M, Kobayashi N, Matsuya S: Myocardial infarction due to coronary thromboarteritis, following acute
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20. Radford DJ, Sondheimer HM, Williams GJ, Fowler RS:
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21. Kitamura S, Kawashima Y, Kawachi K, Fujino M, Kozuka T, Fujita T, Manabe H: Left ventricular function in
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therapy. Am J Dis Child 121:424-427, 1971
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