JOURNAL OF PATHOLOGY,
VOL.163: 9 1-92 (199 1)
EDITORIAL CAT SCRATCH DISEASE Cat scratch disease (CSD) typically affects chil- paracortex, follicular and paracortical hyperplasia, dren with a vesicular skin lesion at the inoculation and vascular proliferation; and (3) neutrophil fragsite, local single lymphadenopathy 2 weeks later, mentation and formation of epithelioid cells (and and spontaneous resolution within 2 4 months. In occasionally giant cells) around the necrotic zones.* about 12 per cent of cases, there is nodal suppu- Thus, in a lymph node, the differential diagnosis of CSD includes tuberculosis and other mycobacterial ration and aspiration may be required.’ The major criteria for diagnosis of CSD have infections; several fungal infections; and yersiniosis, been exposure to cat bite or scratch, an inoculation brucellosis, tularaemia, nocardiosis, Whipple’s dissite, regional lymphadenopathy, typical histopatho- ease, lymphogranuloma venereum, leishmaniasis, logy on lymph node biopsy, negative tests for other herpes simplex infection, sarcoidosis, and Kikuchi’s infections, and a positive delayed hypersensitivity d i ~ e a s e . ~ Atypical, prolonged or recurrent disease is seen in skin test using CSD antigen (this test appears to have sensitivity and specificity approaching 100 per about 5 per cent of CSD cases, adults and children. cent). Since 1983, a further feature has been the The commonest is Parinaud’s oculoglandular synidentification of bacilli, mainly extracellular, drome (the result of inoculation onto the conjuncaround the necrotic zones of nodes and in the skin tiva). Erythema nodosum, atypical pneumonia, pleurisy, synovitis, encephalitis, osteolytic lesions, inoculation sites. Identification of cat scratch bacilli (CSB) depends and mediastinal lymphadenopathy also occur.’ A notable extra-nodal spread of CSD is to the on Warthin-Starry (WS) or Dieterle silver stains. They are seen as pleomorphic < 3 x 0.5 pm rods, liver and spleen; in several children, the features often L- or Y-shaped, arranged in clumps and of fever, abdominal pain, and mild hepatosplenochains.* Buffered formalin is the desired tissue megaly have even developed without any lymphafixative, since B-5 and acidic solutions such as for- denopathy. CT scans show multiple hypoechoic maldehyde/mercuric chloride/acetic acid produce foci, and the portal nodes may be involved. The liver excessive silver deposit. Ordinary Gram methods do histology is similar to that of nodal CSD; granulonot reveal CSB, nor does the Brown-Brenn, but the mas are usually necrotic, with either suppuration or Brown-Hopps modification shows tiny, faintly caseation. When sought in CSD skin test positive Gram-negative rods. Electron microscopy shows cases, WS-positive bacteria have been found. Search rods with a thin cell wall characteristic of Gram- for CSB in non-CSD liver granulomatous histolonegative bacilli, often in blood vessel walls. gies (e.g., primary biliary cirrhosis and sarcoidosis) Culture of CSD nodes in critical broth media has not revealed such bacteria.6 produces colonies of cell-wall-deficient bacilli. Neurological syndromes associated with lymphaInoculated in animals, they produce skin lesions denopathic CSD have been encephalitis (producing similar to those of early human CSD, and bacilli can both focal lesions, and coma from diffuse involvebe reisolated from those lesions; thus, Koch’s postu- ment), transverse myelitis, radiculitis, cerebral lates are fulfilled. Immunocytochemical staining, arteritis (angiographic diagnosis), and optic neuriusing rabbit antibody following immunization with tis.’ The pathogenesis and pathology are obscure cultured CSB, labels the WS-positive bacteria, but since most cases completely recover spontaneously; not a wide range of other necrotizing lymphadeno- in one fatal case, there was acute haemorrhagic pathic infections. CSD patients also demonstrate a leukoencephalitis at autopsy. rise in antibody titre to the agent.3 There is presumably a moderate incidence of subThe pathogenesis of the CSD lymphadenopathy clinical infection by the putative CSB, where a skin is ( I ) subcapsular foci of necrosis with neutrophils; wound does not progress to lymphadenopathy. In (2) spread inwards involving germinal centres and the U.S.A. 36 per cent of cat lovers without history 0022-341 7/91/020091-02$05.00 0 1991 by John Wiley & Sons, Ltd.
92
EDIT0RIAL
of CSD are skin test positive, compared with 0-8per cent of those who dislike cats.' A further dimension to CSD is the description of multiple dermal and subcutaneous WS-positive bacterial lesions in HIV-positive patients; originally termed epithelioid angiomatosis, they are now called bacillary angiomatosis (BA).' Clinically these may resemble Kaposi's sarcoma (KS), but histologically they comprise proliferating small vessels with prominent endothelial cells and variable numbers of neutrophils plus neutrophil debris-but no spindle or slits as seen in KS. They resemble pyogenic granuloma. The bacteria are found extracellularly in clumps, and may be suspected on H&E stains. Morphologically, these bacteria are identical to CSB at the light and electron microscopic level, and label immunocytochemically with anti-CSD sera. Culture produces organisms similar to those grown from non-HIV-associated CSD.9Vascular lesions in HIV-negatives, including pyogenic granuloma, epithelioid haemangioma, and Kimura's disease, have not shown WS-positive bacteria. There is a close pathological analogy between BA and verruga peruana, the angiomatous nodular skin lesion of late infection with Bartonella bacilliformis (bartonellosis), where bacilli are also found. The organisms are distinct, but it suggests a common tissue response to certain bacterial infections. In HIV-positive people, cutaneous BA has been associated with similar lesions extending into underlying bone, disseminated bone marrow BA, lymph node BA, and lesions in pleura, larynx, liver, and ~ p l e e n . Antibiotics ~~'~ cause resolution of lesions. Post-cat scratch lymphadenitis with WS-positive bacteria has also been documented in AIDS patients; notably, the granulomatous component is absent, macrophages are vacuolated (very like nonreactive tuberculosis), and CSB-like bacteria are abundant. In HIV-positives, necropeliotic lesions of the liver associated with CSB are also described. It is probable that infection by the putative CSB is more common than we appreciate. It may account for a significant number of cases of granulomatous hepatitis of unknown aetiology.6 In immunocompetent people, antibiotics are not generally required. In those with atypical manifestations, and those with HIV infection or post-transplant immunodepression, antibiotics such as erythromycin and gentamicin resolve the lesions."
The epidemiological evidence suggests that the CSB are harboured in the oropharynx of healthy cats; are transmitted to humans via a bite or a scratch from claws coated with saliva; and since in temperate zones the disease is seasonal, cats may acquire the organism from certain prey animals. I ' The precise identification of the CSB in human tissues-which may be more than one species-still awaits clarification and correlation with potential agents in the cat oropharynx. So far, we have morphology, immunotyping, and some in vitro cultural information. The new techniques of DNA analysis should provide answers, and place this unusually wide range of clinico-pathological phenomena into a university agreed position within bacterial infections.
S. B. LUCAS Department of Histopathology University College and Middlesex School of Medicine London W1P 7 P N , U.K. REFERENCES 1. Carithers HA. Cat scratch disease. An overview based on a study of 1,200patients. AmJDisChild1985; 139 11241133.
2. Miller-Catchpole R, Variakojis D, Vardiman JW, Loew JM, Carter J . Cat scratch disease. Identification of bacteria in seven cases of lymphadenitis. Am J Surg Patholl986; 1 0 2 7 6 2 8 1 . 3. English CK, Wear DJ, Margileth AM, Lissner CR, Walsh GP. Cat scratch disease. Isolation and culture of bacterial agent. J Am Med Assoc 1988;259 1347-1352. 4 . Lefkowitz M, Wear DJ. Cat-scratch disease masquerading as a solitary tumor of the breast. Arch Pathol Lab Med 1989; 113 4 7 3 4 7 5 . 5 . Margileth AM, Wear DJ, English CK. Systemic cat scratch disease: report of 23 patients with prolonged or recurrent severe bacterial infections. J Infect Dis 1987; 155: 3 9 U 0 2 . 6. Lenoir AA, DeSchryver-Kecskemeti K, Shackleford GD, et al. Granulomatous hepatitis associated with cat scratch disease. Lancet 1988;i:1132-1136. 7. Lewis DW, Tucker SH. Central nervous system involvement in cat scratch disease. Pedialrics 1986; 77: 7 1 6 7 2 1 . 8. LeBoit PE, Berger TG, Egbert BM, Beckstead JH, Yen TSB, Stoler MH. Bacillary angiomatosis. The histopathology and differential diagnosis of a pseudoneoplastic infection in patients with HIV. Am J Surg Pathof 1989; 131: 909-920. 9. Schlossberg D, Krouse TB, Wear DJ, English CK. Culture-proved disseminated cat-scratch disease in AIDS. Arch Intern M e d 1989; 149 1437-1439. 10. Milam MW, Balerdi MJ, Toney JF, Foulis PR, Milam CP, Behnke RH. Epithelioid angiomatosis secondary to disseminated cat scratch disease involving the bone marrow and skin in a patient with AIDS. A m J M e d 1 9 9 0 8 8 18CL183. 11. Kirkpatrick CE, Glickman LT. Cat scratch disease and the role of the domestic cat: vector, reservoir or victim? Med Hyporh 1989 2 8 145-1 49.
VOL.163: 9 1-92 (199 1)
EDITORIAL CAT SCRATCH DISEASE Cat scratch disease (CSD) typically affects chil- paracortex, follicular and paracortical hyperplasia, dren with a vesicular skin lesion at the inoculation and vascular proliferation; and (3) neutrophil fragsite, local single lymphadenopathy 2 weeks later, mentation and formation of epithelioid cells (and and spontaneous resolution within 2 4 months. In occasionally giant cells) around the necrotic zones.* about 12 per cent of cases, there is nodal suppu- Thus, in a lymph node, the differential diagnosis of CSD includes tuberculosis and other mycobacterial ration and aspiration may be required.’ The major criteria for diagnosis of CSD have infections; several fungal infections; and yersiniosis, been exposure to cat bite or scratch, an inoculation brucellosis, tularaemia, nocardiosis, Whipple’s dissite, regional lymphadenopathy, typical histopatho- ease, lymphogranuloma venereum, leishmaniasis, logy on lymph node biopsy, negative tests for other herpes simplex infection, sarcoidosis, and Kikuchi’s infections, and a positive delayed hypersensitivity d i ~ e a s e . ~ Atypical, prolonged or recurrent disease is seen in skin test using CSD antigen (this test appears to have sensitivity and specificity approaching 100 per about 5 per cent of CSD cases, adults and children. cent). Since 1983, a further feature has been the The commonest is Parinaud’s oculoglandular synidentification of bacilli, mainly extracellular, drome (the result of inoculation onto the conjuncaround the necrotic zones of nodes and in the skin tiva). Erythema nodosum, atypical pneumonia, pleurisy, synovitis, encephalitis, osteolytic lesions, inoculation sites. Identification of cat scratch bacilli (CSB) depends and mediastinal lymphadenopathy also occur.’ A notable extra-nodal spread of CSD is to the on Warthin-Starry (WS) or Dieterle silver stains. They are seen as pleomorphic < 3 x 0.5 pm rods, liver and spleen; in several children, the features often L- or Y-shaped, arranged in clumps and of fever, abdominal pain, and mild hepatosplenochains.* Buffered formalin is the desired tissue megaly have even developed without any lymphafixative, since B-5 and acidic solutions such as for- denopathy. CT scans show multiple hypoechoic maldehyde/mercuric chloride/acetic acid produce foci, and the portal nodes may be involved. The liver excessive silver deposit. Ordinary Gram methods do histology is similar to that of nodal CSD; granulonot reveal CSB, nor does the Brown-Brenn, but the mas are usually necrotic, with either suppuration or Brown-Hopps modification shows tiny, faintly caseation. When sought in CSD skin test positive Gram-negative rods. Electron microscopy shows cases, WS-positive bacteria have been found. Search rods with a thin cell wall characteristic of Gram- for CSB in non-CSD liver granulomatous histolonegative bacilli, often in blood vessel walls. gies (e.g., primary biliary cirrhosis and sarcoidosis) Culture of CSD nodes in critical broth media has not revealed such bacteria.6 produces colonies of cell-wall-deficient bacilli. Neurological syndromes associated with lymphaInoculated in animals, they produce skin lesions denopathic CSD have been encephalitis (producing similar to those of early human CSD, and bacilli can both focal lesions, and coma from diffuse involvebe reisolated from those lesions; thus, Koch’s postu- ment), transverse myelitis, radiculitis, cerebral lates are fulfilled. Immunocytochemical staining, arteritis (angiographic diagnosis), and optic neuriusing rabbit antibody following immunization with tis.’ The pathogenesis and pathology are obscure cultured CSB, labels the WS-positive bacteria, but since most cases completely recover spontaneously; not a wide range of other necrotizing lymphadeno- in one fatal case, there was acute haemorrhagic pathic infections. CSD patients also demonstrate a leukoencephalitis at autopsy. rise in antibody titre to the agent.3 There is presumably a moderate incidence of subThe pathogenesis of the CSD lymphadenopathy clinical infection by the putative CSB, where a skin is ( I ) subcapsular foci of necrosis with neutrophils; wound does not progress to lymphadenopathy. In (2) spread inwards involving germinal centres and the U.S.A. 36 per cent of cat lovers without history 0022-341 7/91/020091-02$05.00 0 1991 by John Wiley & Sons, Ltd.
92
EDIT0RIAL
of CSD are skin test positive, compared with 0-8per cent of those who dislike cats.' A further dimension to CSD is the description of multiple dermal and subcutaneous WS-positive bacterial lesions in HIV-positive patients; originally termed epithelioid angiomatosis, they are now called bacillary angiomatosis (BA).' Clinically these may resemble Kaposi's sarcoma (KS), but histologically they comprise proliferating small vessels with prominent endothelial cells and variable numbers of neutrophils plus neutrophil debris-but no spindle or slits as seen in KS. They resemble pyogenic granuloma. The bacteria are found extracellularly in clumps, and may be suspected on H&E stains. Morphologically, these bacteria are identical to CSB at the light and electron microscopic level, and label immunocytochemically with anti-CSD sera. Culture produces organisms similar to those grown from non-HIV-associated CSD.9Vascular lesions in HIV-negatives, including pyogenic granuloma, epithelioid haemangioma, and Kimura's disease, have not shown WS-positive bacteria. There is a close pathological analogy between BA and verruga peruana, the angiomatous nodular skin lesion of late infection with Bartonella bacilliformis (bartonellosis), where bacilli are also found. The organisms are distinct, but it suggests a common tissue response to certain bacterial infections. In HIV-positive people, cutaneous BA has been associated with similar lesions extending into underlying bone, disseminated bone marrow BA, lymph node BA, and lesions in pleura, larynx, liver, and ~ p l e e n . Antibiotics ~~'~ cause resolution of lesions. Post-cat scratch lymphadenitis with WS-positive bacteria has also been documented in AIDS patients; notably, the granulomatous component is absent, macrophages are vacuolated (very like nonreactive tuberculosis), and CSB-like bacteria are abundant. In HIV-positives, necropeliotic lesions of the liver associated with CSB are also described. It is probable that infection by the putative CSB is more common than we appreciate. It may account for a significant number of cases of granulomatous hepatitis of unknown aetiology.6 In immunocompetent people, antibiotics are not generally required. In those with atypical manifestations, and those with HIV infection or post-transplant immunodepression, antibiotics such as erythromycin and gentamicin resolve the lesions."
The epidemiological evidence suggests that the CSB are harboured in the oropharynx of healthy cats; are transmitted to humans via a bite or a scratch from claws coated with saliva; and since in temperate zones the disease is seasonal, cats may acquire the organism from certain prey animals. I ' The precise identification of the CSB in human tissues-which may be more than one species-still awaits clarification and correlation with potential agents in the cat oropharynx. So far, we have morphology, immunotyping, and some in vitro cultural information. The new techniques of DNA analysis should provide answers, and place this unusually wide range of clinico-pathological phenomena into a university agreed position within bacterial infections.
S. B. LUCAS Department of Histopathology University College and Middlesex School of Medicine London W1P 7 P N , U.K. REFERENCES 1. Carithers HA. Cat scratch disease. An overview based on a study of 1,200patients. AmJDisChild1985; 139 11241133.
2. Miller-Catchpole R, Variakojis D, Vardiman JW, Loew JM, Carter J . Cat scratch disease. Identification of bacteria in seven cases of lymphadenitis. Am J Surg Patholl986; 1 0 2 7 6 2 8 1 . 3. English CK, Wear DJ, Margileth AM, Lissner CR, Walsh GP. Cat scratch disease. Isolation and culture of bacterial agent. J Am Med Assoc 1988;259 1347-1352. 4 . Lefkowitz M, Wear DJ. Cat-scratch disease masquerading as a solitary tumor of the breast. Arch Pathol Lab Med 1989; 113 4 7 3 4 7 5 . 5 . Margileth AM, Wear DJ, English CK. Systemic cat scratch disease: report of 23 patients with prolonged or recurrent severe bacterial infections. J Infect Dis 1987; 155: 3 9 U 0 2 . 6. Lenoir AA, DeSchryver-Kecskemeti K, Shackleford GD, et al. Granulomatous hepatitis associated with cat scratch disease. Lancet 1988;i:1132-1136. 7. Lewis DW, Tucker SH. Central nervous system involvement in cat scratch disease. Pedialrics 1986; 77: 7 1 6 7 2 1 . 8. LeBoit PE, Berger TG, Egbert BM, Beckstead JH, Yen TSB, Stoler MH. Bacillary angiomatosis. The histopathology and differential diagnosis of a pseudoneoplastic infection in patients with HIV. Am J Surg Pathof 1989; 131: 909-920. 9. Schlossberg D, Krouse TB, Wear DJ, English CK. Culture-proved disseminated cat-scratch disease in AIDS. Arch Intern M e d 1989; 149 1437-1439. 10. Milam MW, Balerdi MJ, Toney JF, Foulis PR, Milam CP, Behnke RH. Epithelioid angiomatosis secondary to disseminated cat scratch disease involving the bone marrow and skin in a patient with AIDS. A m J M e d 1 9 9 0 8 8 18CL183. 11. Kirkpatrick CE, Glickman LT. Cat scratch disease and the role of the domestic cat: vector, reservoir or victim? Med Hyporh 1989 2 8 145-1 49.
