Bacillary angiomatosis in a child undergoing chemotherapy

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Clinical and laboratory observations

Johnson DE. Medical evaluation of internationally adopted children. N Engl J Med 1991;325:479-85. 6. Nordenfelt E, Dahlquist E. HBsAg-positive adopted children as a cause of intrafamilial spread of hepatitis B. Scand J Infect Dis 1978;10:161-3. 7. Christenson B. Epidemiological aspects of the transmission of hepatitis B by HBsAg-positive adopted children. Scand J Infect Dis 1986;18:105-9. 8. Hershow RC, Hadler SC, Kane MA. Adoption of children

The Journal of Pediatrics October 1992

from countries with endemic hepatitis B: transmission risks and medical issues. Pediatr Infect Dis J 1987;6:431-7. 9. Hepatitis B. In: Peter G, ed. Report of the Committee on Infectious Diseases. 22nd ed. Elk Grove Village, IlL: American Academy of Pediatrics, 1991:238-55. 10. Shafritz DA, Sherman M, Tur-Kaspa R. Hepatitis B virus persistence, chronic liver disease, and primary liver cancer. In: Zakim D, Boyer TD, eds. Hepatology, a textbook of liver disease. 2nd ed. Philadelphia: WB Saunders, 1990:945-58.

Bacillary angiomatosis in a child undergoing

chemotherapy Sarah A. Myers, MD, Neil S. Prose, MD, Julian A. Garcia, MD, Kenneth H. Wilson, MD, Kimberly P. Dunsmore, MD, a n d Hideko Kamino, MD From the Departments of Dermatology, Pediatrics. Pathology, and Medicine, Duke University Medical Center, Durham, North Carolina

Bacillary angiomatosis is an infectious disease of the skin and viscera characterized by vascular lesions, originally described in patients with human immunodeficiency virus infection. There are also case reports of bacillary angiomatosis occurring in immunocompetent patients and in noninfected patients with suppressed immune function. We report a case of bacillary angiomatosis in a child undergoing chemotherapy for acute leukemia. (J PEDIATR1992;121:574-8)

Bacillary angiomatosis is an infectious disorder characterized by cutaneous and visceral vascular lesions. It was originally described in adult patients with human immunodeficiency virus infection. 13 Recent evidence suggests that the agent of bacillary angiomatosis is a rickettsia-like organism, Rochalimaea henselae. 4 Although bacillary angiomatosis is most commonly associated with H I V infection, it has been reported in immunocompetent patients and in non-HIV-infected patients with suppressed immune function. We report herein what we believe to be the first case of bacillary angiomatosis in childhood and the first fully documented case occurring during chemotherapy for malignancy. CASE REPORT A 12-year-old white boy was seen at the pediatric oncology department of Duke University Medical Center with a 5-month hisSubmitted for publication Feb. 21, 1992; accepted May 15, 1992. Reprint requests: Neil S. Prose, MD, Box 3252, Duk e University Medical Center, Durham, NC 27710. 9/22/39305

tory of right foot pain and a 4-week history of malaise, pallor, and increased bruising. Physical examination revealed a pale child with cervical, axillary, and inguinal adenopathy and moderate hepatosplenomegaly. Peripheral blood cell counts revealed a hemoglobin level of 33 gm/L (3.3 gm/dl), leukocyte count of 2.2 x 109/ L (2200/mm 3) with 60% blast forms, and a platelet count of 12 x 109/L (~12,000/ram3). A bone marrow aspirate confirmed the diagnosis of acute CALLA + lymphocytic leukemia. A chest radioI

HIV rRNA

Human immunodeficiency virus Ribosomal ribonucleic acid

I

graph revealed no mediastinal mass, and cytologic examination of ce~ebrospinal fluid showed no malignant cells. Remission was induced with prednisone, 40 mg/m 2 per day for 28 days, vincristine, 1.5 mg/m 2 per week for four doses, L-asparaginase, 6000 I U / m 2 three times weekly for 6 weeks, and 6-mercaptopurine, 75 mg/m 2 for 2 weeks. Methotrexate, cytarabine, and hydrocortisone were given intrathecally for central nervous system prophylaxis. The patient was treated with trimethoprim-sulfamethoxazole three times weekly for pneumocystis pneumonia prophylaxis. Consolidation therapy consisted of methotrexate, 1000 mg/m 2 intravenously, and L-asparaginase, 25,000 IU/m 2 in-

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tramuscularly for six courses. Maintenance therapy included L-asparaginase, 25,000 IU/m 2for six doses, daily 6-mercaptopurine, 75 mg/m 2, weekly methotrexate, 20 mg/m 2, and every-2-months triple intrathecal therapy and every-4-months pulse therapy with vincristine, 1.5 mg/m 2, and prednisone, 40 mg/m 2. The patient tolerated this regimen well and had one self-limited episode of gastroenteritis and one of upper respiratory tract illness during this period of immunosuppression. Eleven months after diagnosis, during the continuation of maintenance therapy, an erythematous nodule developed above the patient's left eyebrow. Initially this lesion was treated with an unknown orally administered antibiotic agent and with topically administered mupirocin, and there was some decrease in the size of the lesion. However, the lesion persisted and the patient's primary physician performed a skin biopsy; the biopsy specimen was interpreted as a fibrous histiocytoma in another institution and no further treatment was given. During the next 6 weeks the lesion enlarged, with associated warmth and drainage. Erythromycin, 250 mg three times daily, was prescribed, and again a decrease in size was noted. Because of the persistence of the lesion, the patient was referred to the Duke University Dermatology Clinic. He had a 1.5 cm firm, violaceous nodule with ulceration and crusting (Fig. 1). The patient was afebrile and had no lymphadenopathy. Laboratory values included a leukocyte count of 2.0 • 109/L (2000/mm 3) with 41% lymphocytes, 41% neutrophils, 16% monocytes, and 2% eosinophils. Histologic review of the previous biopsy specimen revealed multiple fragments of tissue composed almost entirely of a proliferation of small blood vessels lined by plump endothelial cells with rounded, vesicular nuclei. The stroma was fibroblastic and showed scattered lymphocytes and neutrophils (Fig. 2). Deposits of granular, basophilic material were not seen on hematoxylin-and-eosinstained slides. Immunohistochemical stains revealed positivity within the plump endothelial cells for factor VIII and Ulex europaeus (a marker of endothelial cells), supporting the vascular nature of this lesion. Because of the histologic and immunohistochemical findings described above, the diagnosis of bacillary angiomatosis was suspected. Warthin-Starry stain demonstrated the presence of argyrophilic bacilli arranged individually and in clusters characteristic of bacillary angiomatosis 3 (Fig. 2, A [inset]). Transmission electron microscopic study performed on tissue retrieved from the paraffin block revealed the presence of numerous extracellular bacilli with trilaminar walls and the morphologic characteristics previously described in bacillary angiomatosis by LeBoit et al. 3 (Fig. 2, B). Bacterial 16S ribosomal DNA contained in a biopsy specimen was amplified and sequenced as described previously. 5 The sequence of the amplicon was aligned with the partial 16S ribosomal ribonucleic acid sequence of the putative agent for bacillary angiomatosis, BA-TF, 6 by using the NALIGN routine of PCGENE (lntelligenetics, Inc., Mountain View, Calif.). When gaps and ambiguous bases were eliminated, there were 376 bases for comparison of the two sequences; 375 were identical. The one base difference consisted of a guanosine at position 1099 (Escherichia coli 16S rRNA position) in the place of an adenosine found in BA-TF. Position 1099 is moderately strongly conserved. In most eubacteria sequenced so far, including Rochalimaea quintana,

Clinical and laboratory observations

Fig,

5 75

I. Violaceous nodule with ulceration and crusting above left

eyebrow.

a guanosine is incorporated at this position, suggesting that the adenosine found in BA-TF may represent polymerase error. If so, the bases compared were absolutely identical for BA-TF and our organism. Erythromycin, 500 mg twice daily orally, was prescribed. The enzyme-linked immunosorbent assay was negative for HIV. The lesion resolved completely during a period of 6 weeks. DISCUSSION Bacillary angiomatosis may involve either the skin or viscera or both and may be accompanied by systemic symptoms.Z, 7-9 The cutaneous lesions can be solitary or multlple. Superficial lesions usually are bright red papules or nodules that may be smooth surfaced or ulcerated with crusting. The deep lesions are usually skin-colored subcutaneous tumors and may be freely mobile or fixed to underlying structures. The lesion may also appear as a cellulitic plaque that is often tender and erythematous. The superficial lesions are usually far more numerous than the deep lesions, and some patients have several hundred pinpoint papules on the skin. 9 The clinical differential diagnosis of these lesions includes Kaposi sarcoma, pyogenic granuloma, histiocytoid hemangioma, and the second stage of bartonellosis, verruga peruana. Involved internal organs include lymph nodes, liver, spleen, bone, and gastrointestinal tract. 2, 7-9 The diagnosis can be made by skin biopsy. 1~ The typical lesion consists of a proliferation of lobular capillaries with variably plump endothelial cells that protrude into vascular lumina. There is a mixed inflammatory cell infiltrate with neutrophils predominating, often associated with amphophilic granular extracellular aggregates that represent clusters of bacilli demonstrable by Warthin-Starry or related silver stain. Electron microscopy can be used to confirm the morphologic characteristics of the bacillus. The infectious organism responsible for bacillary angiomatosis has been difficult to isolate. A variant of the catscratch disease bacillus was originally postulated to be the causative agent of bacillary angiomatosis. 3 Early investiga-

576

Clinical and laboratory observations

The Journal of Pediatrics October 1992

Fig. 2. A, Small blood vessels lined by plump endothelial cells. There are scattered lymphocytes and neutrophils. (Hematoxylin-eosin stain; X400.) Inset: Clusters of extracellular argyrophilic bacilli. (Warthin-Starry stain.) B, Transmission electron microscopic study shows bacilli between collagen fibers. (x7000.) ln~et: Trilaminar structure of bacterial wall. (x31,000.)

tors noted that tissue sections from patients with bacillary aagiomatosis were stained by immunoperoxidase with the use of antiserum raised against the cat-scratch disease bacillus. 3 However, even before recent molecular characterization studies refuted this notion, important differences between cat-scratch disease and bacillary angiomatosis were noted. Cockerell et al. II cited numerous clinical and histologic differences between bacillary angiomatosis and cat-scratch disease. The rapid response of bacillary angiomatosis to erythromycin is not seen in patients with cat-scratch disease, l, 7, s, 11

The disease that most closely resembles bacillary angiomatosis clinically and histologically is the verruga peruana stage of bartonellosis. The striking similarity of this manifestation of Bartonella infection to bacillary angiomatosis raised the possibility that the diseases are the same. Cockerell et al. 12 demonstrated marked similarity of whole cell fatty acids between organisms of bacillary angiomatosis and Bartonella bacilliformis. Furthermore, the fatty acid profile of the organism causing bacillary angiomatosis was distinct from that of the cat-scratch disease bacillus. Relman et al. 6 used the polymerase chain reaction to

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identify the causative organism of bacillary angiomatosis. Oligonucleotide primers complementary to the 16S rRNA genes of eubacteria were used to amplify 16S ribosomal gene fragments directly from tissue samples of bacillary angiomatosis. The DNA sequence of these fragments was determined and analyzed for phylogenetic relatedness to other known organisms. The agent of bacillary angiomatosis, BA-TF, was found to be most closely related to a rickettsia-like organism, R. quintana. Birtles et al. 13 used the polymerase chain reaction to demonstrate that the agent of bacillary angiomatosis described by Relman et al. is very closely related to but distinct from B. bacilliformis. BA-TF, R. quintana, and B. bacilliformis are all members of the alpha subdivision of proteobacteria in the phylogenetic order Rickettsiales. t3 A collaborative effort by Relman et al. 14 suggested that bacillary angiomatosis, bacillary peliosis hepatis, and a syndrome of fever and bacteremia may be caused by the same organism. A 480-base-pair region of the 16S rRNA gene from an isolate of a patient with bacteremia was enzymatically amplified with primers p93E and p l 3B and its DNA sequence determined. The sequence data suggested that the organism is identical or closely related to strain BA-TF. Recently Welch et al. 4 examined nine strains of Rochalimaea species isolated in blood cultures of adults with septicemia. Eight strains formed a highly related DNA hybridization group indicative of a single previously unrecognized species. The name Rochalimaea henselae was proposed for the new species. In agreement with the data of Relman et al., ~4 the authors proposed that the species includes the etiologic agent of bacillary angiomatosis and parenchymal bacillary peliosis. Our finding of sequences similar to BA-TF by polymerase chain reaction further confirms that a rickettsia-like organism is the cause of bacillary angiomatosis and is in agreement with the more recent data describing R. henselae. The order Rickettsiales includes human pathogens that are commonly transmitted by arthropod vectors. The transmission of R. quintana and B. bacilliformis has been associated with louse infestation and sandfly bite, respectively. R. henselae may also be transmitted by arthropods) 3' 15 Recently, Tappero et al. 16 examined 48 cases of bacillary angiomatosis and found that owning a cat and having a history of recent cat lick, cat scratch, or cat bite were associated with the disease. Although bacillary angiomatosis occurs most commonly in patients with HIV infection, it may be seen in other clinical contexts. Hepatic and splenic bacillary angiomatosis has been reported as a cause of fever of unknown origin in a recipient of a heart transplant.7 Cockerell et al. 11 documented the occurrence of local cutaneous bacillary angiomatosis in an immunocompetent man. Of 48 bacillary an-

Clinical and laboratory observations

5 77

giomatosis cases described by Tappero et al.] 6 five were in immunocompetent patients not infected with HIV. R. henselae bacteremia has been documented in immunocompetent hosts.15 Two previous reports suggested but did not prove that cutaneous bacillary angiomatosis may also occur as a complication of chemotherapy. At least one of four patients reported as displaying "eruptive angiomata in malignant disease" may, in retrospect, have had bacillary angiomatosis. 17 In addition, Omura and Omura 18 discussed a patient who developed numerous vascular nodules while undergoing chemotherapy for lymphoma. Although special stains and electron microscopy were not performed, the authors reasonably speculated that their patient may have had bacillary angiomatosis. The occurrence of vascular nodules in a patient with suppressed immune function, with or without evidence of systemic illness, should suggest the possibility of bacillary angiomatosis. A skin biopsy specimen with a positive WarthinStarry stain will confirm the diagnosis. Prompt treatment with erythromycin will lead to rapid resolution of disease in most cases. REFERENCES

1. Stoler MH, BonfiglioTA, Steigbigel RT, Pereira M. An atypical subcutaneous infection associated with acquired immune deficiency syndrome. Am J Clin Pathol 1983;80:714-8. 2. CockerellCJ, WhitlowMA, Webster GF, Friedman-KienAE. Epithelioid angiomatosis: a distinct vascular disorder in patients with the acquired immunodeficiencysyndromeor AIDSreiated complex. Lancet 1987;2:654-6. 3. LeBoitPE, Berger TG, Egbert BM, et al. Epithelioid haemangioma-like vascular proliferation in AIDS: manifestation of cat scratch disease bacillus infection. Lancet 1988;1:960-3. 4. Welch DF, Pickett DA, Slater LN, Steigerwalt AG, Brenner DJ. Rochalimaea henselae sp. nov., a cause of septicemia, bacillary angiomatosis, and parenchymal bacillary peliosis. J Clin Microbiol 1992;30:275-80. 5. Frothingham R, Allen RL, Wilson KH. Rapid 16S ribosomal DNA sequencing from a single colony without DNA extraction or purification. BioTechniques 1991;11:40-4. 6. Relman DA, Loutitt JS, Schmidt TM, Falkow S, Tompkins LS. The agent of bacillary angiomatosis: an approach to the identification of uncultured pathogens. N Engl J Med 1990; 323:1573-80. 7. Kemper CA, Lombard CM, Deresinski SC, Tompkins LS. Visceral bacillary epithelioid angiomatosis: possible manifestations of disseminated cat-scratch disease in the immunocompromised host: a report of two cases. Am J Med 1990;89: 216-22. 8. Perkocha LA, Geagban SM, Yen TSB, et al. Clinical and pathological features of bacillary peliosishepatis in association with human immunodeficiencyvirus infection. N Engl J Med t 990;323:I58 I-6. 9. Cockerell CJ, LeBoit PE. Bacillary angiomatosis: a newly characterized, pseudoneoplastic,infectious, cutaneous vascular disorder. J Am Acad Dermatol 1990;22:501-12. 10. LeBoit PE, Berger TG, Egbert BM, Beckstead JH, Yen TSB,

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12.

13.

14.

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Stoler MH. Bacillary angiomatosis: the histopathology and differential diagnosis of a pseudoneoplastic infection in patients with human immunodeficiency virus disease. Am J Surg Pathol 1989;13:909-20. Cockerell CJ, Bergstresser PR, Myrie-WilliamsC, Tierno PM. Bacillary epithelioid angiomatosis occurring in an immunocompetent individual. Arch Dermatol 1990;126:787-90. Cockerell C J, Tierno PM, Friedman-Kien AE, Kim KS. Clinical, histologie, microbiologic, and biochemical characterization of the causative agent of bacillary (epithelioid) angiomatosis: a rickettsial illness with features of bartonellosis. J Invest Dermatol 1991 ;97:812-7. Birtles R J, Harrison TG, Taylor AG. The causative agent of bacillary angiomatosis [Letter]. N Engl J Med 1991;325: 1447. Relman DA, Falkow S, Leboit PE, et al. The organism caus-

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15.

16.

17.

18.

ing bacillary angiomatosis, peliosis hepatis, and fever and bacteremia in immunocompromised patients [Letter]. N Engl J Med 1991;324:1514. Lucey D, Dolan M J, Moss CW, et al. Relapsing illness due to Rochalimaea henselae in immunocompetent hosts: implication for therapy and new epidemiological associations. Clin Infect Dis 1992;14:683-8. Tappero JW, Mohle-Boetani J, Koehler J, et al. The epidemiology of bacillary angiomatosis [Abstract]. J Invest Dermatol 1992;98:567. Pembroke AC, Grice K, Levantine AV, Warin AP. Eruptive angiomata in malignant disease. Clin Exp Dermatol 1978;3: t47-56. Omura EF, Omura GA. Human immunodeficiencyvirus-associated skin lesions [Letter]. JAMA 1989;261:991.

Erythrocyte macrocytosis in infants and children with Down syndrome T h o m a s J. S t a r c , MD From the Division of Pediatric Cardiology, Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York

Erythrocyte mean corpuscular volume and mean corpuscular hemoglobin levels were higher in children with Down syndrome than in normal control subjects. Reference values for mean corpuscular volume and mean corpuscular hemoglobin level derived from normal populations may be inappropriate for children with Down syndrome. These findings may have important implications for the diagnosis of iron deficiency in these children. (J PEDIATR1992;121:578-81)

Several investigators have reported erythrocyte macrocytosis in adults 1-5 and children 6, ~ with Down syndrome; however, one group reported no statistically significant increase in erythrocyte size in infants with Down syndrome. 6 The purpose of this study was to assess possible abnormalities in erythrocyte size, as well as other hematologic indexes, in young patients with Down syndrome. Because many of the children with Down syndrome in this study also had heart disease, they were compared with both normal children and children with congenital heart disease.

Submitted for publication Dec. 19, 1991; accepted April 9, 1992. Reprint requests: Thomas J. Starc, MD, Columbia University, Division of Pediatric Cardiology, 630 West 168th St., Babies Hospital, Room 102A South, New York, NY 10032.

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METHODS

Patient population Down syndrome. Sixty-three children with Down syndrome were retrospectively identified from hospital records between January 1986 and February 1990. The diagnosis was confirmed by review of the patient's chart or by interview with the patient's physician. The mean age of the children was 2.1 years and ranged from 0.33 to 6.33 years. Fifty-two children with Down syndrome had congenital heart disease, and 11 had no heart disease. Normal control group. The normal control group consisted of 196 normal children without heart disease between 0.36 and 6.8 years of age who received their primary care in a pediatric clinic in our institution. Children with chronic illnesses and those who had been treated for anemia were excluded~ Cardiac control group. The normal control group con-