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Periarteritis nodosa in infancy
Case Reports PERIARTERITIS REPORT
NODOSA
OF A CASE FOLLOWING
ALLERGIC
IN INFANCY REACTIONS
TO PENICILLIN
LESTER ADELSON, M.D. CLEVELAND, OHIO H E occurrence of periarteritis nodosa (synonyms : polyarteritis, 1, : T panartcritis, 1 polyarteritis nodosa, 8,4 necrotizing arteritis, 5 p r i m a r y arteritis, 6 essential polyarteritis 7) in childhood is an infrequent event. Rothstein and Welt s in 1933 collected f r o m the literature twenty-one cases in children up through the age of 15 years and added two of their own. These twentythree cases comprised 11.8 p e r cent of 195 cases in all age groups found by these authors. Following the appearance of this comprehensive review, individual case reports continued to appear,4, ~, 9, lo, 11 and by 1941 the number of cases in the juvenile age group had risen to f o r t y - f o u r 2 Since that time the incidence of the disease appears to have increased, and childhood periarteritis nodosa has been described b y a n u m b e r of observers within the past decade2, 12, 18, 14, 15, is, 17, is The more frequent diagnosis of periarteritis nodosa in childhood was felt by Rothstein and Welt s to be due not to a greater incidence of the disease but r a t h e r to a more widespread and thorough knowledge of its characteristics and to more careful and complete microscopic examination a t autopsy. Other authors 14, 19 feel t h a t there has been a real increase in the n u m b e r of cases. I n infants u n d e r one y e a r of age periarteritis nodosa is rare. B u t two of the twenty-three cases reported b y Rothstein and Welt s fell into this early age group. Search of the recent literature disclosed only three addiFrom the Laboratory C o u n t y C o r o n e r ' s Office.
of
the
Cuyahoga 346
tional cases in the first year of life. 12, 13 Recently, a 4-month, 13-day-old white male came to a u t o p s y at the Cuyahoga County Coroner's Office and disclosed severe classical periarteritis nodosa. A careful anamnesis furnished b y intelligent a n d observing p a r e n t s pointed toward a f a i r l y definite allergic basis as the probable m a j o r etiological factor. Because of the paucity of infantile cases a n d because the details of the child's illness strongly indicate a probable hypersensitivity to (oral) penicillin as the responsible agent, it is felt t h a t the case is worthy of report. CASE REPORT
V. B. Jr., a 4 ~ - m o n t h - o l d white male, was brought to the Cuyahoga County Morgue with a history of having expired suddenly a n d unexpectedly at home. Past History--The child had been delivered n o r m a l l y following an uneventful gestation. L a b o r had been induced one week p r i o r to the expected date of delivery because eclampsia had developed d u r i n g the m o t h e r ' s one previous p r e g n a n c y two years earlier. A t t h a t time m o u n t i n g hypertension, ankle edema, and a l b u m i n u r i a had indicated the advisability of i n t e r r u p ting p r e g n a n c y at 7 ~ months. L a b o r was artificially started and resulted in the birth of a p r e m a t u r e i n f a n t who survived one day. Three p o s t - p a r t u m convulsions occurred, followed b y complete m a t e r n a l recovery. An kl e edema and albuminuria disappeared, and the blood pressure came down to a normal level where it had remained
ADELSON:
PERIARTERITIS NODOSA IN I N F A N C Y
consistently. The last normal menstrual period occurred in the latter part of January, 1950, and V. B. Jr. was born on Nov. 1, 1950. His birth weight was 5 pounds, 3 ounces, and he left the hospital at the end of a week weighing 5 pounds, 1 ounce. He was started on breast feeding, supplemented by an Olac formula. At the end of four weeks the breast feedings were discontinued, and he was maintained on Olac alone. At six weeks ADC, 5 drops a day, was started, and at ten weeks d r y cereal and strained fruit and vegetables were added. For a brief interval of several days at age seven weeks a new formula of evaporated milk and Dextri-Maltose was tried, but it was soon discontinued, and he was returned to his original diet. During the entire period prior to the onset of his present illness he had always appeared well, developed normally, and gained weight progressively. At two weeks he weighed 6 pounds, at 6 weeks 9 pounds, 15 ounces, at ten weeks 14 pounds, 2 ounces, and at eighteen weeks, ilve days prior to his death, 16 pounds, 10 ounces,
Family
History.--Both
p aren t s
were living and well. The father was 38 years old and the mother 33 years at the time of conception. The maternal grandmother was living with hypertension and " s i n u s i t i s . " The maternal grandfather was living and well. One maternal aunt was said to have died of subacute bacterial endocarditis at 31 years of age following rheumatic f e v e r . B o t h paternal grandparents were dead, the grandmother having died at 68 with carcinoma of the breast, and the grandfather h a v i n g been shot during the late war. There was no history in the grandparents, the parents, or the parents' siblings of any allergic diseases or manifestations save for the " s i n u s i t i s " previously noted. No familial illnesses of any type were brought out by questioning. P r e s e n t I t l n e s s . - - O n Feb. :[9, 1951 the mother noted that the child was
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feverish with a rectal temperature of 102 ~ F. There was slight cough but no rhinorrhea. A moderate degree of cervical adenopathy was noted which persisted throughout the course of the illness. The child was started on 0.62 gr. of aspirin every four hours while awake, and this was continued during the first two weeks of his illness, during which he received a total of 31 11/~ gr. tablets (38.75 gr.) By the next day the temperature had risen to 104 ~ F. The child was examined by a pediatrician who prescribed oral penicillin, 50,000 units every four hours. Twenty-four hours following the institution of penicillin, a discrete punctate and macular rash was noted on the diaper area and within a day it had appeared on the face, ears, back, and legs, meanwhile becoming confluent. The temperature continued steadily elevated at 103 ~ to 104 ~ F., and it was felt that the penicillin might be responsible for both the rash and the fever. It was therefore discontinued after 12 tablets (600,000 units) had been given. The eruption was treated locally with baking soda compresses and a lotion, and it faded within thirty-six hours after the cessation of penicillin. A slight nasal discharge appeared, and NeoSynephrine, 0.25 per cent, was instilled intranasally thrice daily for several days, until the nose no longer discharged. Meanwhile the child was started on Eskadiazine (1 dram, 5 c.c., contains 7~/~ gr. of sulfadiazine), onehalf teaspoon every four hours. On February 26 the Eskadiazine was stopped after having been given for one day, and penicillin was begun once more. Within forty-eight hours a purplish blotchy eruption appeared over the entire face, trunk, and extremities, accompanied by severe conjunctival injection and lacrimation and increased swelling of the cervical glands. The penicillin was once more discontinued after 10 tablets had been given. (The total penicillin administered was 22 tablets or ],100,000 units.) The eruption started to fade
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T H E J O U R N A L OF PEDIATRICS
within seventy-two hours. During this phase of the illness the temperature was maintained steadily at 102 ~ F., and there were frequent episodes of diaphoresis. On March 3 typical urticarial wheals and dermatographia made their appearance. On March 5 the child was started on Benadryl, capsule in his formula every four hours. By March 8 the temperature was normal for the first time since the onset of the illness seventeen days previously, and the child was taken to the pediatrician's office where the only abnormality found was the presence of hives. Clinically, he appeared to have completely recovered from his respiratory infection. Despite the administration of the Benadryl, the hives persisted, and the medication was discontinued on March 9 following two episodes of vomiting, the only such episodes occurring during the entire illness. Syrup of Histadyl (1 c.c. equals 6 mg. thenylpyramine fumarate), 5 to 10 drops every four hours, was substituted. By March 10 the hives were completely gone. Because it was felt that the child might be allergic to his formula, he was tried on evaporated milk and Allerdex from March 9 to 11, and then he was put back on Olac. During the entire period of illness he had taken his feeding well and gained weight. On March 12 he started to refuse his bottle and began to lose ground. The next day, his temperature rose to 102 ~ F., and a 50 mg. Chloromycetin capsu]e was inserted into his rectum, followed by a second capsule in four hours. Following a small poorlytaken evening feeding the child dozed fitfully for a brief interval and then suddenly screamed, became rigid and cyanotic, gasped, and became comatose. Resuscitative efforts by the local fire department with oxygen and carbon dioxide were futile, and the child expired within a few minutes, twentytwo days after the onset of his illness.
Autapsy.-Gross Examination:
External examination disclosed a well-developed
and well-nourished white male infant weighing 151/2 pounds and measuring 26 inches from crown to heel. The only noteworthy external feature was the presence of bilateral hydroceles. Internally, the most striking lesions were located in the heart and lungs. The heart was enlarged in all diameters and presented multiple subendocardial petechiae on the anterior and posterior surfaces. All the major branches of both coronary arteries stood out prominently and presented a conspicuously nodular "beaded" appearance. The vessels were firm to palpation and on cross section showed markedly narrowed lumina except for an aneurysmal dilatation filled with clot in the left circumflex branch. The myocardium w a s uniformly p a 1 e brown and showed no gross evidence of infarct. The ductus arteriosus was closed and there were no congenital cardiac anomalies. The lungs were heavy and subcrepitant. Their cut surfaces were deep purple-red and revealed loci of grayish consolidation. Voluminous quantities of b 1 o o d y frothy fluid exuded on pressure. The thymus displayed multiple petechiae beneath its capsule. The remainder of the gross examination was not remarkable. Microscopic Examination: Multiple sections taken from all portions of the heart disclosed a severe necrotizing arteritis and arteriolitis characteristic of periarteritis nodosa. All the stigmas of the disease were present, e.g., fibrinoid necrosis and edema of the media, extensive inflammatory infiltration in the adventitia and media, aneurysm formation with thrombosis, and intimal proliferation with obliteration of the lumen. In no area was the myocardium infarcted as a result of the vascular disturbance. The veins were not involved by the inflammatory process. In some of the diseased vessels only a sector of the wall was damaged, in others the entire circumference w a s destroyed. Similar necrotizing and proliferative
ADELSON:
PERIARTERITIS I~'ODOSA IN INFANCY
changes were seen in the mesenteric arteries and in the arteries and arterioles of the peri-adrenal fat, the epididymis, prostate, and testis (Fig. 1). The arteries and arterioles in all the other organs of the body including the kidney were completely normal. The lungs were the seat of an extensive bilateral interstitial pneumonia, with p u l m o n a r y congestion, edema, a n d chronic peribronchitis. The mesothelial serosal cells on the
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pleural surface of the diaphragms showed swelling a n d proliferation with the formation of multinucleated giant cells. In the ileum there were focal zones of ulceration with marked inflammatory infiltration into the submucosa. The sinuses of the abdominal lymph nodes and the spleen were filled by an extensive pleomorphic cellular exudate, and there was necrosis of the reticulum cells of the germinal" follicles.
Fig. 1 . - - l ~ e s e n t e r i c a r t e r y ( A ) , t e s t i c u l a r a r t e r y (C), a n d c o r o n a r y a r t e r i e s (B, D, •, F) s h o w i n g c h a r a c t e r i s t i c i n f l a m m a t o r y , necrotizing, a n d p r o l i f e r a t i v e c h a n g e s of p e r i a r t e r i t i s nodosa. (All sections s t a i n e d w i t h h e m a t o x y l i n a n d eosin, X100.)
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THE JOURNAL OF PEDIATRICS
cocci, and a specific infectious process 21 have all been cited as the offendIn summary, a 41/2-month-old in- ing agents, only to be ultimately disfant is presented who died suddenly carded? ~ Relationship to the rheutwenty-two days after the onset of matic group of diseases has been postuwhat appeared to have been an ordi- iated. ~ Selye 2~ states that periarterin a r y u p p e r respiratory infection. tis can be the consequence of exposure During his illness a variety of thera- to a variety of nonspecific noxious peutic agents was administered. The agents. He demonstrated by animal most noteworthy clinical phenomena experimentation that it was possible during the three weeks of the terminal to produce a lesion indistinguishable illness were the appearances of two from periarteritis nodosa by exposure skin eruptions, each following promptto such a nonspecific factor as cold. ly upon the administration of oral and felt that it was " r a t h e r likely, penicillin. The second rash, blotchy therefore, that periarteritis nodosa beand erythematous, was accompanied longs to the so-called diseases of adapb y typical urticaria. At autopsy t a t i o n . " widely disseminated periarteritis noIn 1925 Gruber 26 declared that peridosa was disclosed with the coronary arteritis nodosa was not a disease sui arteries being most seriously involved, generis but that patients with this and bilateral interstitial pneumonia. condition had an increased sensitivity Pathologically the case conforms to of their arteries from a previous inall the criteria laid down for the fection, and that the arterial lesions recognition and diagnosis of periar- were the result of a hyperergic reacteritis nodosa. As has been pointed tion to a variety of toxic and infecout by Miller and Daley, 2~ the patho- tious processes. The past twenty-five logic processes and appearances in years have seen the bulk of medical periarteritis nodosa in childhood are opinion and writing swing toward the similar to those seen in adults, save side of allergy as the factor responthat they are less complicated by de- sible for the spectacular vascular lesgenerative disease. T h e diagnosis ions. The experimental w o r k o f must rest upon the demonstration of Rich and Gregory 27 and of t t o p p s and the characteristic and typical histo- Wissler ~8 and the clinical observations pathologic lesions. 7 Of the four stages of Rich29, 30, 31 and otherslS, 19, 82 all of the disease described by Arkin, ~1 have strengthened the position that the first three, the alterative-degener- hypersensitivity is the crux of the ative, the acute inflammatory, and the m a t t e r in the majority, if not in all granulation tissue stages are w e l l cases of periarteritis nodosa. Although represented. T h e healed end-stage the precise relationships are not comwas not seen, the disease having r u n a pletely understood, experience h a s short fulminating course. shown that there are widely different Of major interest in this case is the types of substances which have the poproblem of etiology and the relation of tentiality of causing periarteritis nothe oral penicillin administration to dosa in man. 19, 20, 29, 30, ~3 The necesthe necrotizing arteritls. In the cen- sary a d j u v a n t factors of constitutional and special tissue susceptibility cannot t u r y which has elapsed since Rokitanbe predetermined clinically. Neale 1~ sky 22 first described the pathology, and suggested the presence of a specifically in the eighty-five years since Kussmaul and Meier 2~ first gave the disease its individualized arterial receptor mechname a n d correlated the clinical anism for this type of allergic reaccourse with gross and microscopic tion. During the decade from 1935 to characteristics, the question of causa1945, t h e sulfonamides a n d horse tion has been a moot point. Parasites, syphilis, viruses, hemolytic strepto- serum were most frequently singled DISCUSSION
ADELSON:
PERIARTERITIS NODOSA IN INFANCY
out as the probable etiological agents. Recently cases of necrotizing arteritis attributed to penicillin have appeared. McCombs 84 has reported two cases in adults who developed periarteritis nodosa, proved by autopsy and biopsy, following the clinical appearance of u n t o w a r d reactions to penicillin. Berne 35 has described necrotizing angiitis in a 53-year-old Italian storekeeper with pneumonia who was treated with penicillin in beeswax-peanut oil and sulfadiazine. He developed a rash following his first injection of the antibiotic, and the drug was discontinued. Following the disappearance of the rash, he was once more started on penicillin, and on the second occasion, he developed a severe bullous erythematous eruption which went on to generalized exfoliation, accompanied by asthma and hives. He died twenty-one days a f t e r the initiation of penicillin t h e r a p y and a t autopsy disclosed severe inflammatory and destructive vascular disease with the coronary arteries showing the most profound changes. The above course of events closely parallels the case reported here, including the appearance of a rash following the first administration of penicillin. While it cannot be categorically stated that the sensitivity in both cases was due to penicillin, nevertheless the history points to it as the most probable etiological agent. The sulfadiazine given in each case was small in amount and certainly in the child would not appear to have played an important p a r t by itself. However, the possibility of its having acted synergistically with the penicillin cannot be eliminated. I f the reaction was due to penicillin, the question of the origin of the sensitivity presents itself. While the ability of penicillin to produce fatal anaphylaxis ~6 and generalized exfoliative dermatitis 37 following previous sensitizing injections is known, neither the child here nor the adult in Berne's ~ case had ever received penicillin prior to his illness, and each reacted to the
351
antibiotic in a hypersensitive fashion following the original administration. A possible explanation is furnished by the work of Gottschalk and Weiss 38 who stated on the basis of patch sensitivity tests carried out on several hundred volunteers that a small percentage of the population is primarily sensitive to penicillin and will react allergically on their first exposure, a phenomenon noted also by Rostenberg and Welch29 The possibility of in utero sensitization was postulated by Wilmer '3 in the case of a 10-day-old child who died with periarteritis nodosa and may account for some cases of p r i m a r y sensitivity. The mother of the infant in the present case gave no history of past penicillin intake. In postulating a hypersensitive state as the basis of periarteritis nodosa, no attempt is made to answer the question why, in a hypersensitive subject, the combination of antigen and antibody is damaging. This is all p a r t of the larger problem of the mechanism of allergy itself, and histologic examination does not provide an answer as to why the damage is precisely and selectively localized in the arterial walls. 19 All that can be stated is the broad generalization that there is an individual constitutional difference in reactivity which determines not only the possibility of sensitization but also the character of the reaction and the tissue in which it will occur. In closing it may be pointed out that the warning uttered by Rich 3~ that " c o n t i n u e d administration of a sulfonamide or of a foreign serum after symptoms o f hypersensitivity have appeared carries the danger of producing visceral damage of the periarteritis nodosa t y p e " applies equally to penicillin and must be kept in mind w h e n allergic manifestations first make their appearance. Continued administration of a drug after symptoms of hypersensitivity have appeared is fraught with danger, and administration must be stopped before irreversible changes appear and irreparable damage has been done.
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T H E J O U R N A L OF PEDIATRICS
SUMMARY A case of p e r i a r t e r i t i s n o d o s a i n a 41/2-month-old w h i t e m a l e is r e p o r t e d . D u r i n g his t e r m i n a l illness w h i c h l a s t e d t w e n t y - t w o days, he w a s t w i c e g i v e n p e n i c i l l i n by m o u t h a n d on each occasion r e a c t e d a l l e r g i c a l l y . T h e p r o b a b l e r e l a t i o n s h i p of t h e d e s t r u c t i v e a r t e r i t i s to t h e p e n i c i l l i n h y p e r s e n s i t i v i t y is p o i n t e d o~t. The microphotographs were made by Mr. Lawrence Johnson, photographer to the Coroner of Cuyahoga County. REFERENCES 1. Laipply, T. C.: Polyarteritis (Periarteritis) Nodosa, ~eview of Clinical and Anatomic Characteristics and Theories of Etiology, Am. Pract. 2: 795, 1948. 2. Heck, Frank J.: Introduction: Symposium on Periarteritis Nodosa, Proc. Staff Meet., Mayo Clin. 24: 17, 1949. 3. Logue, Bruce R., and Mullins, Frank: Polyarteritis Nodosa: Report of Eleven Cases With Review of Recent Literature, Ann. Int. Med. 24: 1], 1946. 4. Barnard, W. G., and Burbury, W. M.: Gangrene of the Fingers and Toes in a Case of Polyarteritis Nodosa, J. Path. & Bact. 39: 284, 1934. 5. Krahulik, Lambert, Rosenthal, Maurice, and Loughlin, Elmer It.: Periarteritis Nodosa (Necrotizing Panarteritis) in Childhood With Meningeal Involvement: Report of a Case With Study of Pathologic Findings, Am. J. M. Sc. .190: 309, ]935. 6. Keith, Haddow M., and Baggenstoss, Archie H.: Primary Arteritis (Periarteritis Nodosa) Among Children, J. PEDIAT. 18" 494, 1941. 7. Wold, Lester E., and Barker, Nelson W.: Periarteritis Nodosa (Essential Polyarteritis): Clinical Data on Thirty Cases Proved at Necropsy, Minnesota Med. 32: 715, 1949. S. Rothstein, Jacob L., and Welt, Sara: Periarteritis Nodosa in Infancy and in Childhood: Report of Two Cases With Necropsy Observations; Abstracts of Cases in the Literature, Am. J. Dis. Child. 45: ]277, 1933. 9. Nowak, T. (Cited by Krahulik et al.): Case of Periarteritis Nodosa With Symptoms of Angina Pectoris in a Child Twelve Years Old, Polska gaz. lek. 12: 579, 2933. 10. u C. Wilfred: - A Case of Periarteritis Nodosa With Subcutaneous Lesions and Recovery, Arch. Dis. Child. 13: 31, 1938.
11. Coe, Meyeron, Reisman, Henry A., and DetIoff, John: Periarteritis Nodosa in a Nine-Year-Old Child, J. PEDIAT. 28: 793, 1941. 12. Scott, Edwin P., and Rotondo, C. C.: Periarteritis Nodosa: Report of Two Cases, One Complicated by Intrapericardial ttemorrhage, J. PEDIAT. 25: 306, 1944. 13. Wilmer, Harry A.: Two Cases of Periarteritis Nodosa Occurring in the First Month of Life, Bull. Johns Hopkins Hosp. 77: 275, 1945. 14. Bradley, Elizabeth J.: Periarteritis Nodosa in Childhood, J. PEDIAT. 31: 78, 1947. 15. Pickard, C. M., Owen, J. G., and Damrain, G . J . : Aneurysms of the Coronary Arteries Due to Polyarteritis Nodosa Occurring in an Infant: Report of a Case With Coronary Artery Thrombosis and Myocardial Infarction, J. Lab. & Clin. Med. 32: 1513, 1947. 16. Taylor, A. W., and Jacoby, N. ~r Acute Polyarteritis Nodosa in Childhood, Lancet 2: 792, 1949. 17. Neale. A. V.: Polyarteritis in Childhood, Arch. Dis. Child. 24: 224, 1949. 18. Kipkie, G. F., and Johnson, D .S.: Possible Pathogenic Mechanisms Responsible for Human Periarteritls Nodosa: As Suggested by the Occurrence of Two Instances of This Disease in Association With Glomerulonephritis, Arch. Path. 51: 387, 1951. 19. Hutchison, H. E.: Polyarteritis Nodosa: A Short Review, Glasgow M. J. 29" 116, 1948.
20. Miller, Henry G., and Daley, Raymond: Clinical Aspects of Polyarteritis Nodosa, Quart. J. Med. 15: 255, 1946. 21. Arkin, Aaron: A Clinical and Pathological Study of Periarteritis Nodosa: A Report of Five Cases, One Histologically Healed, Am. J. Path. 6: 401, 1930. 22. Von Rokitansky, C. (Cited by Laipply): Ueber eiaige der wichtigsten Erkrankungen der Arterien, Deakschr. d. k. Akad. d. Wissensch. 4: 49, 1852. 23. Kussmaul, A., and Meier, R. (Cited by Wold and Barker): Ueber eine bisher nicht beschriebene eigenthiimliche Arterienerkrankung (Periarteritis Nodosa), die mit Morbus Brightii und rapid fortschreitender allgemeiner Muskelli~hmung einhergeht, Deutsches Arch. f. klin. Med. 1: 484, 1866. 24. Middleton, William S., and McCarter, John C.: The Diagnosis of Periarteritis Nodosa, Am. J. M. Sc. 190: 291, 1935. 25. Selye, Hans: The General Adaptation Syndrome and the Diseases of Adaptation, J. Clin. Endocrinol. 6: 117, 1946. 26. Gruber, G. B. (Cited by Rothstein and Welt): Virchows Arch. f. path. Anat. 258: 441, 1925.
ADELSON:
PERIARTERITIS NODOSA IN INFANCY
27. Rich, Arnold R., a n d Gregory, J o h n E.: The E x p e r i m e n t a l Demonstration T h a t P e r i a r t e r i t i s l~odosa Is a M a n i f e s t a t i o n of H y p e r s e n s i t i v i t y , Bull. John.s Hopkins Hosp. 72: 65, 1942. 28. Hopps, H. C., a n d Wissler, R. W.: The E x p e r i m e n t a l Production of Generalized A r t e r i t i s and P e r i a r t e r i t i s ( P e r i a r t e r i t i s l~odosa), J. Lab. & Clio. Med. 31: 939, 1946. 29. Rich, Arnold R.: The Role of Hypers e n s i t i v i t y in P e r i a r t e r i t i s Nodosa as I n d i c a t e d b y Seven Cases Developing During Serum Sickness and Sulfonamide Therapy, Bull. J o h n s Hopkins Hosp. 71: 123, 1942. 30. Rich, Arnold R.: Additional Evidence of the Role of H y p e r s e n s i t i v i t y in the Etiology of P e r i a r t e r i t i s N o d o s a : A n o t h e r Case Associated W i t h a Sulfonamide Reaction, Bull. J o h n s Hopkins Hosp. 71: 375, ]942. 31. Rich, Arnold R.: Hypersen.sitivity to Iodine as a Cause of P e r i a r t e r i t i s Nodosa, Bull. J o h n s Hopkins Hosp. 77: 43, ] 945. 32. Diaz-Rivera, R. S., and l~iller, A. J.: P e r i a r t e r i t i s Nodosa: A C]inicopathological Analysis of Seven Cases, Ann. I n t . Med. 24: 420, 1946.
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33. Van Wyk, Judson J., and Hoffmann, C. Rowell: P e r i a r t e r i t i s Nodosa, a Case of F a t a l Exfoliative Dermatitis Resulting From ' ' Dilantin Sodium ' ' Sensitization, Arch. Int. 1Y[ed. 81: 605, 1948. 34. 1VfcCombs, Robert P.: Drug Allergies: Case Reports of Unusual Sequelae in Three Patients, Bull. New England Med. Center 13: 39, 1951. 35. Berne, Robert IV[.: An Unusual Sensit i v i t y Reaction to Penicillin: Report of a Case W i t h Autopsy Findings, New E n g l a n d J. Med. 242: 814, 1950. 36. Waldbott, George L.: Anaphylactic D e a t h From Penicillin, J. A. M. A. 139: 526, 1949. 37. Rabinovitch, Jacob, a n d Snitkoff, Morris C.: Acute E x f o l i a t i v e Dermat i t i s and Death Following Penicillin Therapy, J. A. IVL A. 138: 496, 1948. 38. Gottschalk, Helen Reller, and Weiss, Richard S.: Epidermal S e n s i t i v i t y to Penicillin, Arch. Dermat. & Syph. 53: 365, 1946. 39. Rostenberg, Adolph, Jr., a n d Welch, H e n r y : A Study ~)f the Types of Hyp e r s e n s i t i v i t y Induced b y Penicillin, Am. J. M. Sc. 210: 157. lO~t5
NODOSA
OF A CASE FOLLOWING
ALLERGIC
IN INFANCY REACTIONS
TO PENICILLIN
LESTER ADELSON, M.D. CLEVELAND, OHIO H E occurrence of periarteritis nodosa (synonyms : polyarteritis, 1, : T panartcritis, 1 polyarteritis nodosa, 8,4 necrotizing arteritis, 5 p r i m a r y arteritis, 6 essential polyarteritis 7) in childhood is an infrequent event. Rothstein and Welt s in 1933 collected f r o m the literature twenty-one cases in children up through the age of 15 years and added two of their own. These twentythree cases comprised 11.8 p e r cent of 195 cases in all age groups found by these authors. Following the appearance of this comprehensive review, individual case reports continued to appear,4, ~, 9, lo, 11 and by 1941 the number of cases in the juvenile age group had risen to f o r t y - f o u r 2 Since that time the incidence of the disease appears to have increased, and childhood periarteritis nodosa has been described b y a n u m b e r of observers within the past decade2, 12, 18, 14, 15, is, 17, is The more frequent diagnosis of periarteritis nodosa in childhood was felt by Rothstein and Welt s to be due not to a greater incidence of the disease but r a t h e r to a more widespread and thorough knowledge of its characteristics and to more careful and complete microscopic examination a t autopsy. Other authors 14, 19 feel t h a t there has been a real increase in the n u m b e r of cases. I n infants u n d e r one y e a r of age periarteritis nodosa is rare. B u t two of the twenty-three cases reported b y Rothstein and Welt s fell into this early age group. Search of the recent literature disclosed only three addiFrom the Laboratory C o u n t y C o r o n e r ' s Office.
of
the
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tional cases in the first year of life. 12, 13 Recently, a 4-month, 13-day-old white male came to a u t o p s y at the Cuyahoga County Coroner's Office and disclosed severe classical periarteritis nodosa. A careful anamnesis furnished b y intelligent a n d observing p a r e n t s pointed toward a f a i r l y definite allergic basis as the probable m a j o r etiological factor. Because of the paucity of infantile cases a n d because the details of the child's illness strongly indicate a probable hypersensitivity to (oral) penicillin as the responsible agent, it is felt t h a t the case is worthy of report. CASE REPORT
V. B. Jr., a 4 ~ - m o n t h - o l d white male, was brought to the Cuyahoga County Morgue with a history of having expired suddenly a n d unexpectedly at home. Past History--The child had been delivered n o r m a l l y following an uneventful gestation. L a b o r had been induced one week p r i o r to the expected date of delivery because eclampsia had developed d u r i n g the m o t h e r ' s one previous p r e g n a n c y two years earlier. A t t h a t time m o u n t i n g hypertension, ankle edema, and a l b u m i n u r i a had indicated the advisability of i n t e r r u p ting p r e g n a n c y at 7 ~ months. L a b o r was artificially started and resulted in the birth of a p r e m a t u r e i n f a n t who survived one day. Three p o s t - p a r t u m convulsions occurred, followed b y complete m a t e r n a l recovery. An kl e edema and albuminuria disappeared, and the blood pressure came down to a normal level where it had remained
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PERIARTERITIS NODOSA IN I N F A N C Y
consistently. The last normal menstrual period occurred in the latter part of January, 1950, and V. B. Jr. was born on Nov. 1, 1950. His birth weight was 5 pounds, 3 ounces, and he left the hospital at the end of a week weighing 5 pounds, 1 ounce. He was started on breast feeding, supplemented by an Olac formula. At the end of four weeks the breast feedings were discontinued, and he was maintained on Olac alone. At six weeks ADC, 5 drops a day, was started, and at ten weeks d r y cereal and strained fruit and vegetables were added. For a brief interval of several days at age seven weeks a new formula of evaporated milk and Dextri-Maltose was tried, but it was soon discontinued, and he was returned to his original diet. During the entire period prior to the onset of his present illness he had always appeared well, developed normally, and gained weight progressively. At two weeks he weighed 6 pounds, at 6 weeks 9 pounds, 15 ounces, at ten weeks 14 pounds, 2 ounces, and at eighteen weeks, ilve days prior to his death, 16 pounds, 10 ounces,
Family
History.--Both
p aren t s
were living and well. The father was 38 years old and the mother 33 years at the time of conception. The maternal grandmother was living with hypertension and " s i n u s i t i s . " The maternal grandfather was living and well. One maternal aunt was said to have died of subacute bacterial endocarditis at 31 years of age following rheumatic f e v e r . B o t h paternal grandparents were dead, the grandmother having died at 68 with carcinoma of the breast, and the grandfather h a v i n g been shot during the late war. There was no history in the grandparents, the parents, or the parents' siblings of any allergic diseases or manifestations save for the " s i n u s i t i s " previously noted. No familial illnesses of any type were brought out by questioning. P r e s e n t I t l n e s s . - - O n Feb. :[9, 1951 the mother noted that the child was
347
feverish with a rectal temperature of 102 ~ F. There was slight cough but no rhinorrhea. A moderate degree of cervical adenopathy was noted which persisted throughout the course of the illness. The child was started on 0.62 gr. of aspirin every four hours while awake, and this was continued during the first two weeks of his illness, during which he received a total of 31 11/~ gr. tablets (38.75 gr.) By the next day the temperature had risen to 104 ~ F. The child was examined by a pediatrician who prescribed oral penicillin, 50,000 units every four hours. Twenty-four hours following the institution of penicillin, a discrete punctate and macular rash was noted on the diaper area and within a day it had appeared on the face, ears, back, and legs, meanwhile becoming confluent. The temperature continued steadily elevated at 103 ~ to 104 ~ F., and it was felt that the penicillin might be responsible for both the rash and the fever. It was therefore discontinued after 12 tablets (600,000 units) had been given. The eruption was treated locally with baking soda compresses and a lotion, and it faded within thirty-six hours after the cessation of penicillin. A slight nasal discharge appeared, and NeoSynephrine, 0.25 per cent, was instilled intranasally thrice daily for several days, until the nose no longer discharged. Meanwhile the child was started on Eskadiazine (1 dram, 5 c.c., contains 7~/~ gr. of sulfadiazine), onehalf teaspoon every four hours. On February 26 the Eskadiazine was stopped after having been given for one day, and penicillin was begun once more. Within forty-eight hours a purplish blotchy eruption appeared over the entire face, trunk, and extremities, accompanied by severe conjunctival injection and lacrimation and increased swelling of the cervical glands. The penicillin was once more discontinued after 10 tablets had been given. (The total penicillin administered was 22 tablets or ],100,000 units.) The eruption started to fade
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T H E J O U R N A L OF PEDIATRICS
within seventy-two hours. During this phase of the illness the temperature was maintained steadily at 102 ~ F., and there were frequent episodes of diaphoresis. On March 3 typical urticarial wheals and dermatographia made their appearance. On March 5 the child was started on Benadryl, capsule in his formula every four hours. By March 8 the temperature was normal for the first time since the onset of the illness seventeen days previously, and the child was taken to the pediatrician's office where the only abnormality found was the presence of hives. Clinically, he appeared to have completely recovered from his respiratory infection. Despite the administration of the Benadryl, the hives persisted, and the medication was discontinued on March 9 following two episodes of vomiting, the only such episodes occurring during the entire illness. Syrup of Histadyl (1 c.c. equals 6 mg. thenylpyramine fumarate), 5 to 10 drops every four hours, was substituted. By March 10 the hives were completely gone. Because it was felt that the child might be allergic to his formula, he was tried on evaporated milk and Allerdex from March 9 to 11, and then he was put back on Olac. During the entire period of illness he had taken his feeding well and gained weight. On March 12 he started to refuse his bottle and began to lose ground. The next day, his temperature rose to 102 ~ F., and a 50 mg. Chloromycetin capsu]e was inserted into his rectum, followed by a second capsule in four hours. Following a small poorlytaken evening feeding the child dozed fitfully for a brief interval and then suddenly screamed, became rigid and cyanotic, gasped, and became comatose. Resuscitative efforts by the local fire department with oxygen and carbon dioxide were futile, and the child expired within a few minutes, twentytwo days after the onset of his illness.
Autapsy.-Gross Examination:
External examination disclosed a well-developed
and well-nourished white male infant weighing 151/2 pounds and measuring 26 inches from crown to heel. The only noteworthy external feature was the presence of bilateral hydroceles. Internally, the most striking lesions were located in the heart and lungs. The heart was enlarged in all diameters and presented multiple subendocardial petechiae on the anterior and posterior surfaces. All the major branches of both coronary arteries stood out prominently and presented a conspicuously nodular "beaded" appearance. The vessels were firm to palpation and on cross section showed markedly narrowed lumina except for an aneurysmal dilatation filled with clot in the left circumflex branch. The myocardium w a s uniformly p a 1 e brown and showed no gross evidence of infarct. The ductus arteriosus was closed and there were no congenital cardiac anomalies. The lungs were heavy and subcrepitant. Their cut surfaces were deep purple-red and revealed loci of grayish consolidation. Voluminous quantities of b 1 o o d y frothy fluid exuded on pressure. The thymus displayed multiple petechiae beneath its capsule. The remainder of the gross examination was not remarkable. Microscopic Examination: Multiple sections taken from all portions of the heart disclosed a severe necrotizing arteritis and arteriolitis characteristic of periarteritis nodosa. All the stigmas of the disease were present, e.g., fibrinoid necrosis and edema of the media, extensive inflammatory infiltration in the adventitia and media, aneurysm formation with thrombosis, and intimal proliferation with obliteration of the lumen. In no area was the myocardium infarcted as a result of the vascular disturbance. The veins were not involved by the inflammatory process. In some of the diseased vessels only a sector of the wall was damaged, in others the entire circumference w a s destroyed. Similar necrotizing and proliferative
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PERIARTERITIS I~'ODOSA IN INFANCY
changes were seen in the mesenteric arteries and in the arteries and arterioles of the peri-adrenal fat, the epididymis, prostate, and testis (Fig. 1). The arteries and arterioles in all the other organs of the body including the kidney were completely normal. The lungs were the seat of an extensive bilateral interstitial pneumonia, with p u l m o n a r y congestion, edema, a n d chronic peribronchitis. The mesothelial serosal cells on the
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pleural surface of the diaphragms showed swelling a n d proliferation with the formation of multinucleated giant cells. In the ileum there were focal zones of ulceration with marked inflammatory infiltration into the submucosa. The sinuses of the abdominal lymph nodes and the spleen were filled by an extensive pleomorphic cellular exudate, and there was necrosis of the reticulum cells of the germinal" follicles.
Fig. 1 . - - l ~ e s e n t e r i c a r t e r y ( A ) , t e s t i c u l a r a r t e r y (C), a n d c o r o n a r y a r t e r i e s (B, D, •, F) s h o w i n g c h a r a c t e r i s t i c i n f l a m m a t o r y , necrotizing, a n d p r o l i f e r a t i v e c h a n g e s of p e r i a r t e r i t i s nodosa. (All sections s t a i n e d w i t h h e m a t o x y l i n a n d eosin, X100.)
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THE JOURNAL OF PEDIATRICS
cocci, and a specific infectious process 21 have all been cited as the offendIn summary, a 41/2-month-old in- ing agents, only to be ultimately disfant is presented who died suddenly carded? ~ Relationship to the rheutwenty-two days after the onset of matic group of diseases has been postuwhat appeared to have been an ordi- iated. ~ Selye 2~ states that periarterin a r y u p p e r respiratory infection. tis can be the consequence of exposure During his illness a variety of thera- to a variety of nonspecific noxious peutic agents was administered. The agents. He demonstrated by animal most noteworthy clinical phenomena experimentation that it was possible during the three weeks of the terminal to produce a lesion indistinguishable illness were the appearances of two from periarteritis nodosa by exposure skin eruptions, each following promptto such a nonspecific factor as cold. ly upon the administration of oral and felt that it was " r a t h e r likely, penicillin. The second rash, blotchy therefore, that periarteritis nodosa beand erythematous, was accompanied longs to the so-called diseases of adapb y typical urticaria. At autopsy t a t i o n . " widely disseminated periarteritis noIn 1925 Gruber 26 declared that peridosa was disclosed with the coronary arteritis nodosa was not a disease sui arteries being most seriously involved, generis but that patients with this and bilateral interstitial pneumonia. condition had an increased sensitivity Pathologically the case conforms to of their arteries from a previous inall the criteria laid down for the fection, and that the arterial lesions recognition and diagnosis of periar- were the result of a hyperergic reacteritis nodosa. As has been pointed tion to a variety of toxic and infecout by Miller and Daley, 2~ the patho- tious processes. The past twenty-five logic processes and appearances in years have seen the bulk of medical periarteritis nodosa in childhood are opinion and writing swing toward the similar to those seen in adults, save side of allergy as the factor responthat they are less complicated by de- sible for the spectacular vascular lesgenerative disease. T h e diagnosis ions. The experimental w o r k o f must rest upon the demonstration of Rich and Gregory 27 and of t t o p p s and the characteristic and typical histo- Wissler ~8 and the clinical observations pathologic lesions. 7 Of the four stages of Rich29, 30, 31 and otherslS, 19, 82 all of the disease described by Arkin, ~1 have strengthened the position that the first three, the alterative-degener- hypersensitivity is the crux of the ative, the acute inflammatory, and the m a t t e r in the majority, if not in all granulation tissue stages are w e l l cases of periarteritis nodosa. Although represented. T h e healed end-stage the precise relationships are not comwas not seen, the disease having r u n a pletely understood, experience h a s short fulminating course. shown that there are widely different Of major interest in this case is the types of substances which have the poproblem of etiology and the relation of tentiality of causing periarteritis nothe oral penicillin administration to dosa in man. 19, 20, 29, 30, ~3 The necesthe necrotizing arteritls. In the cen- sary a d j u v a n t factors of constitutional and special tissue susceptibility cannot t u r y which has elapsed since Rokitanbe predetermined clinically. Neale 1~ sky 22 first described the pathology, and suggested the presence of a specifically in the eighty-five years since Kussmaul and Meier 2~ first gave the disease its individualized arterial receptor mechname a n d correlated the clinical anism for this type of allergic reaccourse with gross and microscopic tion. During the decade from 1935 to characteristics, the question of causa1945, t h e sulfonamides a n d horse tion has been a moot point. Parasites, syphilis, viruses, hemolytic strepto- serum were most frequently singled DISCUSSION
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PERIARTERITIS NODOSA IN INFANCY
out as the probable etiological agents. Recently cases of necrotizing arteritis attributed to penicillin have appeared. McCombs 84 has reported two cases in adults who developed periarteritis nodosa, proved by autopsy and biopsy, following the clinical appearance of u n t o w a r d reactions to penicillin. Berne 35 has described necrotizing angiitis in a 53-year-old Italian storekeeper with pneumonia who was treated with penicillin in beeswax-peanut oil and sulfadiazine. He developed a rash following his first injection of the antibiotic, and the drug was discontinued. Following the disappearance of the rash, he was once more started on penicillin, and on the second occasion, he developed a severe bullous erythematous eruption which went on to generalized exfoliation, accompanied by asthma and hives. He died twenty-one days a f t e r the initiation of penicillin t h e r a p y and a t autopsy disclosed severe inflammatory and destructive vascular disease with the coronary arteries showing the most profound changes. The above course of events closely parallels the case reported here, including the appearance of a rash following the first administration of penicillin. While it cannot be categorically stated that the sensitivity in both cases was due to penicillin, nevertheless the history points to it as the most probable etiological agent. The sulfadiazine given in each case was small in amount and certainly in the child would not appear to have played an important p a r t by itself. However, the possibility of its having acted synergistically with the penicillin cannot be eliminated. I f the reaction was due to penicillin, the question of the origin of the sensitivity presents itself. While the ability of penicillin to produce fatal anaphylaxis ~6 and generalized exfoliative dermatitis 37 following previous sensitizing injections is known, neither the child here nor the adult in Berne's ~ case had ever received penicillin prior to his illness, and each reacted to the
351
antibiotic in a hypersensitive fashion following the original administration. A possible explanation is furnished by the work of Gottschalk and Weiss 38 who stated on the basis of patch sensitivity tests carried out on several hundred volunteers that a small percentage of the population is primarily sensitive to penicillin and will react allergically on their first exposure, a phenomenon noted also by Rostenberg and Welch29 The possibility of in utero sensitization was postulated by Wilmer '3 in the case of a 10-day-old child who died with periarteritis nodosa and may account for some cases of p r i m a r y sensitivity. The mother of the infant in the present case gave no history of past penicillin intake. In postulating a hypersensitive state as the basis of periarteritis nodosa, no attempt is made to answer the question why, in a hypersensitive subject, the combination of antigen and antibody is damaging. This is all p a r t of the larger problem of the mechanism of allergy itself, and histologic examination does not provide an answer as to why the damage is precisely and selectively localized in the arterial walls. 19 All that can be stated is the broad generalization that there is an individual constitutional difference in reactivity which determines not only the possibility of sensitization but also the character of the reaction and the tissue in which it will occur. In closing it may be pointed out that the warning uttered by Rich 3~ that " c o n t i n u e d administration of a sulfonamide or of a foreign serum after symptoms o f hypersensitivity have appeared carries the danger of producing visceral damage of the periarteritis nodosa t y p e " applies equally to penicillin and must be kept in mind w h e n allergic manifestations first make their appearance. Continued administration of a drug after symptoms of hypersensitivity have appeared is fraught with danger, and administration must be stopped before irreversible changes appear and irreparable damage has been done.
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T H E J O U R N A L OF PEDIATRICS
SUMMARY A case of p e r i a r t e r i t i s n o d o s a i n a 41/2-month-old w h i t e m a l e is r e p o r t e d . D u r i n g his t e r m i n a l illness w h i c h l a s t e d t w e n t y - t w o days, he w a s t w i c e g i v e n p e n i c i l l i n by m o u t h a n d on each occasion r e a c t e d a l l e r g i c a l l y . T h e p r o b a b l e r e l a t i o n s h i p of t h e d e s t r u c t i v e a r t e r i t i s to t h e p e n i c i l l i n h y p e r s e n s i t i v i t y is p o i n t e d o~t. The microphotographs were made by Mr. Lawrence Johnson, photographer to the Coroner of Cuyahoga County. REFERENCES 1. Laipply, T. C.: Polyarteritis (Periarteritis) Nodosa, ~eview of Clinical and Anatomic Characteristics and Theories of Etiology, Am. Pract. 2: 795, 1948. 2. Heck, Frank J.: Introduction: Symposium on Periarteritis Nodosa, Proc. Staff Meet., Mayo Clin. 24: 17, 1949. 3. Logue, Bruce R., and Mullins, Frank: Polyarteritis Nodosa: Report of Eleven Cases With Review of Recent Literature, Ann. Int. Med. 24: 1], 1946. 4. Barnard, W. G., and Burbury, W. M.: Gangrene of the Fingers and Toes in a Case of Polyarteritis Nodosa, J. Path. & Bact. 39: 284, 1934. 5. Krahulik, Lambert, Rosenthal, Maurice, and Loughlin, Elmer It.: Periarteritis Nodosa (Necrotizing Panarteritis) in Childhood With Meningeal Involvement: Report of a Case With Study of Pathologic Findings, Am. J. M. Sc. .190: 309, ]935. 6. Keith, Haddow M., and Baggenstoss, Archie H.: Primary Arteritis (Periarteritis Nodosa) Among Children, J. PEDIAT. 18" 494, 1941. 7. Wold, Lester E., and Barker, Nelson W.: Periarteritis Nodosa (Essential Polyarteritis): Clinical Data on Thirty Cases Proved at Necropsy, Minnesota Med. 32: 715, 1949. S. Rothstein, Jacob L., and Welt, Sara: Periarteritis Nodosa in Infancy and in Childhood: Report of Two Cases With Necropsy Observations; Abstracts of Cases in the Literature, Am. J. Dis. Child. 45: ]277, 1933. 9. Nowak, T. (Cited by Krahulik et al.): Case of Periarteritis Nodosa With Symptoms of Angina Pectoris in a Child Twelve Years Old, Polska gaz. lek. 12: 579, 2933. 10. u C. Wilfred: - A Case of Periarteritis Nodosa With Subcutaneous Lesions and Recovery, Arch. Dis. Child. 13: 31, 1938.
11. Coe, Meyeron, Reisman, Henry A., and DetIoff, John: Periarteritis Nodosa in a Nine-Year-Old Child, J. PEDIAT. 28: 793, 1941. 12. Scott, Edwin P., and Rotondo, C. C.: Periarteritis Nodosa: Report of Two Cases, One Complicated by Intrapericardial ttemorrhage, J. PEDIAT. 25: 306, 1944. 13. Wilmer, Harry A.: Two Cases of Periarteritis Nodosa Occurring in the First Month of Life, Bull. Johns Hopkins Hosp. 77: 275, 1945. 14. Bradley, Elizabeth J.: Periarteritis Nodosa in Childhood, J. PEDIAT. 31: 78, 1947. 15. Pickard, C. M., Owen, J. G., and Damrain, G . J . : Aneurysms of the Coronary Arteries Due to Polyarteritis Nodosa Occurring in an Infant: Report of a Case With Coronary Artery Thrombosis and Myocardial Infarction, J. Lab. & Clin. Med. 32: 1513, 1947. 16. Taylor, A. W., and Jacoby, N. ~r Acute Polyarteritis Nodosa in Childhood, Lancet 2: 792, 1949. 17. Neale. A. V.: Polyarteritis in Childhood, Arch. Dis. Child. 24: 224, 1949. 18. Kipkie, G. F., and Johnson, D .S.: Possible Pathogenic Mechanisms Responsible for Human Periarteritls Nodosa: As Suggested by the Occurrence of Two Instances of This Disease in Association With Glomerulonephritis, Arch. Path. 51: 387, 1951. 19. Hutchison, H. E.: Polyarteritis Nodosa: A Short Review, Glasgow M. J. 29" 116, 1948.
20. Miller, Henry G., and Daley, Raymond: Clinical Aspects of Polyarteritis Nodosa, Quart. J. Med. 15: 255, 1946. 21. Arkin, Aaron: A Clinical and Pathological Study of Periarteritis Nodosa: A Report of Five Cases, One Histologically Healed, Am. J. Path. 6: 401, 1930. 22. Von Rokitansky, C. (Cited by Laipply): Ueber eiaige der wichtigsten Erkrankungen der Arterien, Deakschr. d. k. Akad. d. Wissensch. 4: 49, 1852. 23. Kussmaul, A., and Meier, R. (Cited by Wold and Barker): Ueber eine bisher nicht beschriebene eigenthiimliche Arterienerkrankung (Periarteritis Nodosa), die mit Morbus Brightii und rapid fortschreitender allgemeiner Muskelli~hmung einhergeht, Deutsches Arch. f. klin. Med. 1: 484, 1866. 24. Middleton, William S., and McCarter, John C.: The Diagnosis of Periarteritis Nodosa, Am. J. M. Sc. 190: 291, 1935. 25. Selye, Hans: The General Adaptation Syndrome and the Diseases of Adaptation, J. Clin. Endocrinol. 6: 117, 1946. 26. Gruber, G. B. (Cited by Rothstein and Welt): Virchows Arch. f. path. Anat. 258: 441, 1925.
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PERIARTERITIS NODOSA IN INFANCY
27. Rich, Arnold R., a n d Gregory, J o h n E.: The E x p e r i m e n t a l Demonstration T h a t P e r i a r t e r i t i s l~odosa Is a M a n i f e s t a t i o n of H y p e r s e n s i t i v i t y , Bull. John.s Hopkins Hosp. 72: 65, 1942. 28. Hopps, H. C., a n d Wissler, R. W.: The E x p e r i m e n t a l Production of Generalized A r t e r i t i s and P e r i a r t e r i t i s ( P e r i a r t e r i t i s l~odosa), J. Lab. & Clio. Med. 31: 939, 1946. 29. Rich, Arnold R.: The Role of Hypers e n s i t i v i t y in P e r i a r t e r i t i s Nodosa as I n d i c a t e d b y Seven Cases Developing During Serum Sickness and Sulfonamide Therapy, Bull. J o h n s Hopkins Hosp. 71: 123, 1942. 30. Rich, Arnold R.: Additional Evidence of the Role of H y p e r s e n s i t i v i t y in the Etiology of P e r i a r t e r i t i s N o d o s a : A n o t h e r Case Associated W i t h a Sulfonamide Reaction, Bull. J o h n s Hopkins Hosp. 71: 375, ]942. 31. Rich, Arnold R.: Hypersen.sitivity to Iodine as a Cause of P e r i a r t e r i t i s Nodosa, Bull. J o h n s Hopkins Hosp. 77: 43, ] 945. 32. Diaz-Rivera, R. S., and l~iller, A. J.: P e r i a r t e r i t i s Nodosa: A C]inicopathological Analysis of Seven Cases, Ann. I n t . Med. 24: 420, 1946.
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33. Van Wyk, Judson J., and Hoffmann, C. Rowell: P e r i a r t e r i t i s Nodosa, a Case of F a t a l Exfoliative Dermatitis Resulting From ' ' Dilantin Sodium ' ' Sensitization, Arch. Int. 1Y[ed. 81: 605, 1948. 34. 1VfcCombs, Robert P.: Drug Allergies: Case Reports of Unusual Sequelae in Three Patients, Bull. New England Med. Center 13: 39, 1951. 35. Berne, Robert IV[.: An Unusual Sensit i v i t y Reaction to Penicillin: Report of a Case W i t h Autopsy Findings, New E n g l a n d J. Med. 242: 814, 1950. 36. Waldbott, George L.: Anaphylactic D e a t h From Penicillin, J. A. M. A. 139: 526, 1949. 37. Rabinovitch, Jacob, a n d Snitkoff, Morris C.: Acute E x f o l i a t i v e Dermat i t i s and Death Following Penicillin Therapy, J. A. IVL A. 138: 496, 1948. 38. Gottschalk, Helen Reller, and Weiss, Richard S.: Epidermal S e n s i t i v i t y to Penicillin, Arch. Dermat. & Syph. 53: 365, 1946. 39. Rostenberg, Adolph, Jr., a n d Welch, H e n r y : A Study ~)f the Types of Hyp e r s e n s i t i v i t y Induced b y Penicillin, Am. J. M. Sc. 210: 157. lO~t5