Chapter 257. Cat Scratch Disease (Bartonella Henselae)

Cat scratch disease (CSD) is a ubiquitous, self-limited infection characterized by prolonged regional lymphadenitis and often an inoculation site papule, usually after a cat’s (frequently a kitten’s) scratch or bite, and caused primarily by Bartonella henselae. In 10% to 20% of cases, the lymph node will suppurate.1,2 In a minority of cases (approximately 10%), a wide range of extranodal manifestations collectively known as atypical CSD may occur, including fever of unknown origin, as well as visceral, neurologic, and ocular involvement. In immune competent individuals, prognosis is generally good, but infection may be life-threatening and its manifestations different in the immune compromised.

Epidemiology and Pathophysiology

CSD occurs worldwide and is prevalent in warm and humid climates. In temperate zones, CSD occurs primarily during fall and winter, sometimes also during the summer, while in the tropics, it occurs throughout the year.1-3 CSD was, in the past, considered to be mainly a disease of children and adolescents, about 55% males, with approximately 90% of patients younger than 18 to 21 years old.1 Newer studies, however, have reported that 45% and 43% of CSD patients are more than 18 and 20 years of age, respectively.4,5 CSD almost never occurs in children under 2 years of age and is increasingly recognized in all age groups, including the elderly.6 Intrafamilial clustering of CSD occurs rarely,7 though anti-B henselae seropositivity is more frequent in families with a case of CSD than in the general population, indicative of asymptomatic infection.5 Immune deficient people, especially those with HIV, may become severely ill with a unique spectrum of disease.2,8 In 1993, the annual incidence of CSD in the United States was estimated at 9 to 10/100,000 with about 10% hospitalization, and most patients were younger than 21 years old.4 However, indirect transmission of B henselae by red cell transfusion may be possible.19 In 2000, the US annual hospitalization rate for CSD was estimated at 0.6/100,000 and 0.86/100,000 for children under 18 and under 5 years old, respectively; not surprisingly 24% of admissions were for atypical disease, 12% central nervous system (CNS) and 7% visceral.9 Cats, especially kittens under 1 year of age, are the major reservoir and tend to have prolonged, asymptomatic intraerythrocytic bacteremia. They infect humans by scratch, bite, or mucous membrane (conjunctival, respiratory) inoculation.2,5,10-14 The cat flea, Ctenocephalides felis, is associated with increased cat infectivity and with cat-to-cat transmission of B henselae although it probably does not play a major role in cat-to-human B henselae transmission.5,11,15 The observation that in temperate zones CSD incidence peaks in fall and winter while flea infestation of cats primarily occurs during spring and summer argues against the role of the cat flea in human CSD pathogenesis. Felids, dogs, monkeys, and other animals may harbor B henselae, and some have been anecdotally associated with CSD. Inanimate objects (eg, thorns, splinters, fencing) probably also cause CSD, though overall, approximately 90% of CSD is cat associated.16 Certain ticks can harbor B henselae, but their role in human disease is as yet undefined.17,18 Direct human-to-human spread has not been reported; however, indirect transmission of B henselae by red cell transfusion may be possible.19

Bartonellae are fastidious, slow-growing, pleomorphic gram-negative Proteo bacteria, related to Brucella. All Bartonella spp can be cultured on cell-free media (eg, rabbit-heart infusion or chocolate agar plates). Results are optimized if media are fresh. Culture of B henselae may require several weeks of incubation before colonies can be detected. Routine bacterial cultures in the clinical microbiology laboratory are not likely to detect Bartonella growth. Although B henselae can be frequently isolated from infected cats, sensitivity of blood or lymph node cultures is extremely low in immunocompetent patients with cat scratch disease (CSD). Therefore, cultures are not recommended for the routine diagnosis of most CSD cases.20B bacilliformis, B quintana, and B henselae are the most important human pathogens, but other Bartonellae (eg, B elizabethiae, B kohlerae, and B clarridgeiae) also cause human disease.20 CSD was clinically recognized in the early 20th century and was first described in 1950 by Debré.21 In 1983, organisms were visualized by silver staining of CSD lymph nodes.22 In 1988, Afipia felis, a rare cause of CSD, was isolated,23 and finally, in the 1990s, B henselae was proven the major cause of CSD—epidemiologically, serologically, by culture, and by molecular methods.20 Recently, B. clarridgeiae was reported to be another minor cause of CSD.24 The pathogenesis of CSD is poorly understood, and the reasons some patients develop typical CSD with localized infection and regional necrotizing granulomatous adenitis while others develop serious atypical disease, presumably due to blood-borne dissemination with visceral or other end-organ involvement, is not clear. Bacterial and host factors play a role. B henselae strains particularly associated with human disease (eg, ST1 genotype) or with only cat infection (eg, ST7 genotype) were identified.25 The type and severity of the host immune response to infection also modify the clinical picture.26,27 Immunocompromised individuals, especially those with cell-mediated immune deficiency, either congenital or acquired (especially HIV-AIDS), are at risk of developing severe or atypical disease.2,20,28B henselae can infect and persist in CD34+ differentiating hematopoietic progenitor cells29; like other Bartonellae, it interacts with endothelial cells and is capable of inducing angiogenesis.30B henselae can induce a Th1 inflammatory response, and IFNg and nitric oxide play important roles.30,31 Dendritic cells and humoral immunity also play a role in the host response to B henselae.32

Clinical Features

Typical cat scratch disease (CSD) is probably the most common cause of prolonged subacute regional lymphadenitis in children.2,33 Cutaneous inoculation of B henselae is 90% cat, especially kitten-associated, 50% to 75% of which is via scratch or bite.1,2,16,33 A few days to a few weeks later, often unrecognized by the patient, a 2- to 5-mm erythematous, nonpainful papule appears at the inoculation site in up to two thirds of patients (Figure 257-1) and persists for a few weeks.1,2,16,33B henselae can be found in these lesions (Fig. 257-1). When inoculation is presumably respiratory and involves mucous membranes (especially about the head and neck), inoculation lesions are absent. The hallmark of typical CSD is chronic regional lymphadenitis in a node or nodes draining the site of inoculation. Most frequently, CSD involves a solitary lymph node or a group of nodes at a single site, while only rarely will CSD manifest as generalized adenopathy.1,2 Usually tender initially, often remaining tender, these nodes appear from 1 week to 1 to 2 months after inoculation. Size may vary from 1 to 2 cm to 5 to 10 cm, and erythema of the overlying skin may occur (eFigs. 257.1 and 257.2). Suppuration occurs in 10% to 20%1,2,16,33 and drainage of pus may persist for weeks. CSD is primarily an infection of the nodes draining the upper extremity, head, neck, and groin, but any lymph node location is possible.1,2,16,33 Epitrochlear lymphadenopathy with or without axillary adenopathy is typical though not pathognomonic of CSD (eFigure 257.3). Between 30% and 50% of patients will have an elevated temperature that can be accompanied by malaise, anorexia, night sweats, headache and other nonspecific complaints, all of which are more prominent with increasing age.1,2,16 Resolution is usually over weeks to a few months, though rarely, recovery may be prolonged, over a year or more.

Typical Csd

The causes of regional adenopathy/adenitis with or without an inoculation lesion are numerous.34,35 The prolonged course of CSD lymphadenopathy, often without the stigmata of pyogenic lymphadenitis (eg, local erythema, warmth, and leukocytosis), particularly when accompanied by fever, night sweats, or weight loss, may mimic malignancy, especially lymphoma, and is often a cause of serious concern for both the patient, the parents, and the treating physician. Maintaining a high index of suspicion and taking a detailed history, particularly that of cat contact, are important in making the correct diagnosis and thus avoiding diagnostic procedures that are often unnecessary (eg, computerized tomography [CT] scan, biopsies). Infection is most commonly the cause of regional adenopathy/adenitis: bacterial—staphylococcal, streptococcal, Erysipelothrix rhusiopathiae, possibly tularemia, brucellosis, plague, syphilis, Lyme disease, LGV, anthrax; higher bacteria—actinomycosis, nocardia; mycobacterial—tuberculosis and especially atypical mycobacteria (usually in the very young, < 3 years old); fungal—blastomycosis, histoplasmosis, coccidiomycosis, sporotrichosis; viral—EBV, CMV, HIV; parasitic—toxoplasmosis. The possibility of malignancy, especially lymphoma, or of a benign tumor must be entertained. Noninfectious, nonneoplastic causes include sarcoidosis, Kawasaki disease, sinus histiocytosis with massive lymphadenopathy, congenital neck anomalies, autoimmune lymphoproliferative syndrome, histiocytic necrotizing lymphadenitis (Kikuchi disease), sometimes possibly due to B henselae,36 idiopathic facial aseptic granuloma, and drug-induced lymphadenopathy (eg, due to phenytoin). Other than as suggested by one recent report,34 CSD rarely coexists with another pathological entity.

Complicated Csd

The term atypical CSD (cat scratch disease) is confusing and should be replaced by “extranodal CSD” or “complicated CSD.” In immune competent children, typical CSD (regional lymphadenopathy) occurs in 85% to 90%, and atypical or complicated CSD in the remainder.1,2,16,33 Occasionally, B henselae disseminates to liver, spleen, eye, CNS, bone, and other sites. Even these manifestations are usually self-limited, and recovery without sequelae is usually the rule. The most common atypical presentation of CSD (about 50% of all atypical CSD) is Parinaud oculoglandular syndrome (eFig. 257.4), where the patient has granulomatous conjunctivitis and preauricular lymphadenitis.2,37,38 In fact, this is actually typical CSD with conjunctival inoculation and regional adenitis. Dissemination to viscera usually involves liver or spleen, often with prolonged fever, abdominal pain, weight loss, and tender visceromegaly, sometimes abnormal hepatocellular enzymes, elevated ESR or CRP, and frequently without an inoculation site or regional adenopathy.2,39,40 Ultrasound and CT suggest microabscesses, which histologically are necrotizing granulomata of liver or spleen. CSD is a common cause of FUO in children, and FUO due to CSD may occur in the context of visceral dissemination or in its absence.2,41-48 Eye manifestations other than conjunctivitis include neuroretinitis, papillitis, optic neuritis, focal retinochoroiditis, where most commonly the patient complains of acute, usually unilateral, visual deterioration, and occurs in about 2% of CSD. Optic nerve edema with stellate macular exudates (“macular star”) is seen funduscopically and can persist for months. This is associated with sequelae in some, though most recover.2,37,42,43 Neurologic complications (2–4% of CSD) include encephalopathy with or without focal or generalized seizures, transverse myelitis, radiculitis, cerebellar ataxia, cranial nerve palsies especially of the facial nerve, and compression neuropathy.2,44-47 These presentations can occur with or without typical CSD symptoms or signs. Encephalopathy, the most common neurologic complication, usually begins abruptly 1 to 4 weeks after exposure to B henselae. Lumbar puncture is either normal or with a mild, predominantly mononuclear pleocytosis, or mildly elevated CSF protein. Culture is negative, CT is normal, and electroencephalogram (EEG) is characteristically encephalopathic. Most recover within weeks to months, sequelae are rare, but CNS involvement can be fatal.48 CSD should be considered in any previously healthy school-aged child with new onset status epilepticus.49 Other atypical manifestations of CSD consist of osteomyelitis/osteolytic granulomatous lesions including those of vertebrae and pelvis,50,51 possibly multifocal osteomyelitis52; numerous rashes including erythema nodosum, erythema multiforme, and vasculitic53,54; deep neck space infection; arthropathy and musculoskeletal complaints (mostly in adults)55,56; hypercalcemia57; pneumonitis, thrombocytopenic purpura, hemolytic anemia, glomerulonephritis.2,58B henselae has also been associated with Henoch Schönlein purpura as determined in 2 small studies where the seropositivity rate for B henselae was found to be significantly higher than controls.59,60 Two very important kinds of B henselae infection not within the scope of this chapter are bacterial endocarditis, rare in children,2,20,33,61 and infection of immunocompromised patients including vascular proliferative cutaneous and visceral lesions of bacillary angiomatosis and bacillary peliosis, and persisting or relapsing bacteremia.2,20,33

Diagnostic Evaluation

Historically, diagnosis was made when a patient presented with a cat scratch or bite, a primary inoculation lesion, regional lymphadenitis and a characteristic biopsy, sterile pus or a positive skin test with cat scratch antigen. Clinical suspicion in the appropriate epidemiological context is still extremely important, but given the expanded spectrum of CSD, specific diagnostic tools are required, especially when a classical history is absent. Routine laboratory tests are usually not helpful: WBC, ESR, CRP may be normal or elevated, hepatocellular enzymes may be abnormal with visceral involvement, and imaging (ultrasound, CT, magnetic resonance imaging [MRI]) is also nonspecific (eFig. 257.5). Culture of B henselae from blood or tissue is slow, cumbersome, requires special and impractical techniques, and in the immune competent host, negative cultures are the rule rather than the exception. Skin test (prepared from pus aspirated from affected lymph nodes of CSD patients) was deemed useful, but because it was never standardized and is potentially dangerous, its use has been discontinued, especially with current, better diagnostic tools available.2,5 Biopsy of the inoculation papule or lymph node (or deep lesions) shows a characteristic but nondiagnostic histological picture with epithelioid granuloma and Langhan giant cells. Later, necrotizing stellate granulomata are seen, and in some nodes, microabscesses enlarge and coalesce, leading to suppuration. The inflammatory process often involves surrounding tissue (eg, the skin). When present (primarily early in the course of infection), B henselae may be visualized by silver staining, but a positive stain for bacteria is not specific.20 Immunohistochemical assays can improve specificity but are of limited availability in routine diagnostic laboratories.20 The most practical way to diagnose CSD is serologically. The IgG-based immunofluorescent antibody test (IFAT), such as that performed at the Centers for Disease Control and Prevention, has a sensitivity of 84% to 95% and a specificity of 94% to 98%.20 Results from studies performed in Europe are less satisfactory and inconsistent, perhaps due to higher background seroprevalence.62,63 Cross-reactivity with other organisms including Bartonellae (eg, B quintana) has been reported.20 Enzyme immunoassay (EIA) tests are also used, but variable sensitivity is also a problem.64 An outer-membrane protein-based EIA has a sensitivity of 85% (when IgG and/or IgM anti-B henselae antibodies are positive) and a specificity of 98% and can be useful in differentiating old from acute disease.65,66 Both IFAT and EIA antibodies develop slowly; thus, seroconversion may occur only after ⩾ 3 weeks of illness. Repeat serological testing may be required to make the diagnosis. Polymerase chain reaction (PCR) of lymph node or pus aspirate, primary skin lesions or of other tissue is a highly sensitive and specific diagnostic tool. Both broad-range and species-specific PCR assays have been developed. It is particularly useful when serology is negative and definitive diagnosis is urgent (eg, in those who are particularly ill, who have atypical disease or complications, whose lesions are not resolving, the immune compromised, or when other diagnoses such as malignancy are being entertained).67,68 Fine-needle aspiration of a lesion for PCR and cultures may suffice, although excisional biopsy is indicated when malignancy needs to be ruled out. One difficulty is in considering the diagnosis of CSD, particularly atypical CSD, in the absence of cat exposure or lymphadenopathy.

Treatment

Few studies, mostly small, anecdotal, or retrospective, have addressed the question of therapy for CSD. In addition, in vitro susceptibility testing does not correlate with in vivo results of therapy.69 Possible explanations include the fact that lymph node disease may be host-response driven, that most antibiotics are not bactericidal for Bartonellae, and that the intracellular location of the bacteria may be protective. A large, retrospective study showed that treating with rifampin, ciprofloxacin, gentamicin, and trimethoprim-sulfamethoxazole resulted in a shorter duration of disease when compared to no therapy or to therapy with other antimicrobials.70 However, it is difficult to draw conclusions from this retrospective review, especially because CSD is a self-limited disease, and cure without sequelae is the rule even without treatment. Only one small, randomized, prospective, double-blind, placebo-controlled study was performed to assess the effects of treating CSD: azithromycin reduced lymph node volume significantly during 30 days posttherapy. Thereafter, there were no differences noted.71 Antimicrobial therapy for CSD has been reviewed critically, and some specific recommendations for therapy have been made.70,72 It is logical to conclude, due to the minimal effects of antibiotic therapy on typical CSD (a self-limited disease with a good prognosis), that many if not most nonimmunocompromised patients need not be treated. Treatment should be limited to patients with moderate to severe illness who have not begun to improve spontaneously (eg, those with severe systemic symptoms, those whose nodes are large and significantly painful). Azithromycin (10 mg/kg on day 1, 5 mg/kg on days 2 through 5) seems to be a reasonable choice if treatment for typical CSD is desired. Doxycycline, rifampin, ciprofloxacin, gentamicin, and trimethoprim-sulfamethoxazole may be considered as alternatives. However, despite antimicrobial treatment, many CSD patients have a prolonged course or develop lymph node suppuration or complications. Symptomatic therapy including analgesics (eg, NSAIDS) and locally applied warm compresses can relieve pain. Aspiration of fluctuant, suppurating nodes with a 16- to 18-gauge needle (with 5% lidocaine-prilocaine cream, with or without midazolam) yields thick, beige, odorless, often blood-tinged pus and will relieve the associated discomfort (eFig. 257.6). This may need to be repeated up to 2 to 3 times. Incision and drainage should be avoided in order to prevent sinus formation with chronic drainage. For the treatment of complicated CSD, no strong evidence-based recommendations can be made, though various protocols have been proposed.70,72 Rarely, a Jarisch-Herxheimer reaction can occur.35 Bacteremia, which is only rarely detected in CSD, has been treated with 4 weeks of either azithromycin or doxycycline, occasionally with aminoglycosides. Hepatosplenic CSD has been treated with rifampin ± gentamicin or trimethoprim-sulfamethoxazole.40 Treating neuroretinitis may decrease the incidence and severity of sequelae and a combination of doxycycline and rifampin for 4 to 6 weeks is recommended for adults, though a regimen for children younger than 8 years old has not been defined.70,72 CNS complications are often treated similarly but for shorter durations, though evidence to support this is lacking. Corticosteroids have been of benefit anecdotally,73 but their use should not be considered routinely. It must be emphasized that the treatment of endocarditis due to B henselae, or of immunocompromised patients with B henselae infection including bacillary angiomatosis, peliosis, and bacteremia is not within the scope of this chapter.

In healthy individuals, especially in the pediatric age group, a good prognosis is the rule. Even atypical disease or complications usually resolve without sequelae. Patience is required because the infection’s course often spans weeks to months. If not immunocompromised, lifelong immunity is nearly 100%, and reinfection or relapse is exceedingly rare. In the immunocompromised, infection may be life threatening, and immunity may not develop.

People play no role in transmitting infection to other people, and therefore, isolation of a CSD patient makes no sense. Avoiding cats, especially kittens, is an excellent way to prevent CSD but is not always practical. Preventing flea infestation may indirectly diminish a cat’s infectivity and theoretically may also directly prevent cat-to-human infection. Declawing may be partially protective. Vaccination of cats to prevent B henselae infection is not available. Because intrafamilial clustering is rare, removal of the cat from the household should not be necessary. When immunocompromised patients or patients with valvular heart disease are involved, older, less potentially infective cats (> 1 year old) might make safer pets than would kittens.