AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Catscratch disease (CSD) is associated with a self-limited subacute solitary or regional lymphadenopathy. The patient usually has a history of sustaining a scratch or bite from a cat or kitten.

Pathophysiology

The hallmark of catscratch disease is regional adenopathy proximal to the site of inoculation.

In immunocompetent patients, Bartonella infection causes a granulomatous and suppurative response. In immunocompromised patients, the response can be vasculoproliferative with neovascularization.

Bartonella is able to promote angioproliferation through adhesion A, which is observed in bacillary angiomatosis, peliosis, and verruga peruana.

Nine outer membrane proteins (OMP) for Bartonella henselae have been identified. The 43 kD OMP is a major protein capable of binding endothelial cells and needs further investigation to clarify its role in pathogenesis of catscratch disease.

Frequency

United States

An estimated 9.3 cases per 100,000 population occur each year, representing 22,000 cases annually with approximately 2,000 hospitalizations per year.

Most cases occur in the fall and winter.

International

Catscratch disease has been reported worldwide; however, the international incidence is unknown. The disease is more prevalent in areas with warm humid climates.

Mortality/Morbidity

Catscratch disease is typically a benign self-limited disorder in immunocompetent people. Symptoms usually resolve within 2-4 months.

Of affected patients, 5-25% experience a course complicated by involvement of sites other than regional lymph nodes.

Patients older than 60 years are more likely to present with atypical features of catscratch disease.

Immunocompromised hosts may develop more serious forms of infection with B henselae or Bartonella quintana, such as bacillary angiomatosis, bacillary peliosis, or bacteremia.

Race

Incidence is higher in whites.

Sex

Catscratch disease is reported more frequently in males, who account for approximately 60% of all cases.

Age

In a database analysis by Jackson et al, 55% of catscratch disease patients were aged 18 years or younger. More cases than previously recognized may exist in adults. Most studies have focused primarily on pediatric populations.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Most patients give a history of exposure to cats (eg, recent cat scratch, bite, lick).
• One or more 3- to 5-mm red-brown nontender papules develop on most patients at the site of inoculation 3-10 days after the bacteria are introduced.
• Within 1-3 weeks, lymphadenopathy develops in the nodal group, draining the inoculum site. Lymphadenopathy often consists of a single node and can be moderately tender, with erythema and increased warmth of the overlying skin. Lymphadenopathy should resolve within 2-4 months but in rare cases, lasts up to 6-12 months.
• Up to 10% of nodes may suppurate and require needle aspiration.
• Other symptoms might include the following:
• • Malaise/fatigue (29.4%)
  • Fever (28%)
  • Anorexia (14.5%)
  • Headache (13%)
  • Sore throat (7%)
  • Arthralgia (2.5%)

Physical

• Fever may be present, and in one series of 1,200 cases, only 9% of patients had a fever higher than 39°C.
• In 1-3 weeks, the inoculum site lesions evolve through erythematous, vesicular, and papular-crusted changes.
• When patients present with the complaint of painful adenopathy, the original site of inoculation may not be apparent.
• Nodes draining the site of inoculation enlarge within 1-3 weeks of contact with the kitten or cat. The upper extremities are the most common location (46% axillary and epitrochlear nodes), followed by the neck and jaw region (26% cervical and submandibular nodes), the groin (17.5% femoral and inguinal), preauricular region (7%), and clavicular region (2%). In 10-20% of cases, more than one region is affected. Node size is typically 1-5 cm but may enlarge to 8-10 cm.
• The following are forms of atypical catscratch disease, which occurs in 5-25% of cases:
• • Parinaud oculoglandular syndrome: This syndrome affects 5-10% of patients with catscratch disease and is the most common form of atypical catscratch disease. Parinaud syndrome is characterized by preauricular lymphadenopathy and unilateral granulomatous conjunctivitis. Although this syndrome can be caused by other infections, B henselae is the most common etiologic agent.
  • Neuroretinitis: Unilateral painless vision loss occurs with central scotoma, optic disc swelling, or macular star referred to as Leber neuroretinitis or idiopathic stellate neuroretinitis. Patients usually recover vision completely within 1-3 months.
  • Acute encephalopathy: Predominant symptom is rapid progression of headache to lethargy and coma. Seizures and even status epilepticus can occur in these patients. CSF may be normal or may have a lymphocytic pleocytosis. CT scan and MRI findings are usually normal, and the course is generally self-limited without neurologic sequelae. However, persistent cognitive impairment and death have been reported in some cases. Myelitis, radiculitis, compression neuropathy, and cerebellar ataxia have been reported.
  • Bartonella endocarditis: This condition should be considered in patients with manifestations of endocarditis, negative blood culture results, and regular contact with cats. Possible risk factors are alcoholism, homelessness, and body louse infestation. Patients with Bartonella endocarditis often require valve replacement.
  • Visceral involvement: This usually entails systemic symptoms combined with multiple hypoechogenic-hypodense hepatic or splenic lesions. The liver is described as having a "nutmeg" appearance with stellate necrotizing granulomata on the histologic examination. This syndrome may develop in the absence of lymphadenopathy.
  • Bone and joint involvement: Osteolytic lesions can be seen at various sites, and vertebral osteomyelitis with epidural abscess may occur in these cases. Catscratch disease-associated arthropathy may also occur.
  • Skin: Various skin manifestations occur in approximately 5% of patients with catscratch disease. These manifestations include nonspecific rashes, erythema nodosum, and leukocytoclastic vasculitis.
• Immunocompromised patients such as those with cancer, persons who have undergone transplantation, and persons with HIV may develop bacillary angiomatosis, bacillary peliosis, or persistent or relapsing fever with bacteremia.
• • Bacillary angiomatosis: This vasculoproliferative disease mostly involves the skin but can involve the other organs. It manifests as numerous brown to violaceous tumors of the skin and subcutaneous tissues. Without antibiotic therapy, the disease progresses with dissemination. The lesions are very similar to verruga peruana, the chronic form of Carrión disease (Oroya fever) from Bartonella bacilliformis infection.
  • Bacillary peliosis: This condition involves the solid internal organs with reticuloendothelial elements (usually the liver, but the spleen, abdominal lymph nodes, and bone marrow may also be involved). Vasculoproliferation of sinusoidal hepatic capillaries resulting in blood-filled spaces in the liver can occur in this condition.
  • Persistent or relapsing fever with bacteremia: This is another distinct clinical syndrome in immunocompromised individuals.

Causes

• Catscratch disease is most commonly caused by B henselae, formerly known as Rochalimaea henselae. In the genus Bartonella, B bacilliformis, B quintana, Bartonella elizabethae, Bartonella vinsonii, and Bartonella koehlerae are also responsible for human disease.
• In 1993, Dolan et al isolated B henselae from lymph nodes of patients with catscratch disease. Bartonella species are small pleomorphic, fastidious, facultative, gram-negative, and intracellular bacilli. Infection appears to confer lifelong immunity, as reports of recurrences of clinical catscratch disease are rare.
• Domestic cats are the natural reservoir and vectors of B henselae. In cats, the infection is asymptomatic. Transmission between cats is thought to be from fleas, and seroprevalence in cats is highest in warm or humid climates, where incidence of cat flea infestation is higher.
• Transmission from cats to humans occurs by a scratch or bite when the bacterium is present on the claws or oral cavity. Kittens younger than 12 months are 15 times more likely to transmit the disease than adult cats. Kittens are more likely to be bacteremic with B henselae and they are more likely to scratch. Individuals who had been scratched or bitten by a kitten are 27 times more likely to become infected, and people who had at least one kitten with fleas were 29 times more likely to become infected than people whose animals were free of fleas.
• Human to human transmission has not been reported and no data support transmission from fleas to humans.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Lymphoma
Histiocytic Necrotizing Lymphadenitis (Kikuchi-Fujimoto disease)
Nontuberculous mycobacteria
Bacterial adenitis
Cutaneous anthrax
Erysipelothrix rhusiopathiae
Viral infections: Orf (Parapoxvirus), Cowpox (Orthopoxvirus)

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• In addition to lymphadenopathy of greater than or equal to 10 mm present for greater than equal to 3 weeks, 3 of 4 of the following criteria confirm the diagnosis of catscratch disease. Three confirm the diagnosis; in an atypical case, all 4 of the following criteria may be needed:
• • Contact with a cat with or without a scratch mark or a regional inoculation lesion (skin papule, eye granuloma, mucous membrane)
  • Laboratory and radiology findings: Negative purified protein derivative (PPD) or serology for other infectious causes of adenopathy; sterile pus aspirated from node; PCR assay for Bartonella positive; CT scan with liver or spleen abscesses
  • Positive enzyme immunoassay or indirect fluorescent antibody assay serology test greater than 1:64; a fourfold rise in titer between acute and convalescent specimens
  • Biopsy of node, skin, liver, bone, or eye granuloma showing granulomatous inflammation compatible with catscratch disease; positive Warthin-Starry silver stain
• Indirect fluorescent antibody (IFA) test (96% sensitive by CDC) and enzyme-linked immunosorbent assay (ELISA, 71% sensitive) are used for detection of serum antibody to B henselae. A high antibody titer of greater than 1:64 is suggestive of recent infection. Paired acute and convalescent sera (drawn 6 wk apart) showing a fourfold or greater increase is confirmatory. With IFA and ELISA tests, some cross reactivity may occur between Bartonella species (especially, B henselae and B quintana) and other bacteria such as Chlamydia psittaci.
• Polymerase chain reaction (PCR) is the most sensitive test and is also able to differentiate between different Bartonella species, as well as subspecies and strains. However, this test is not readily available.
• Presumptive diagnosis of infection with catscratch disease bacilli can be made with Warthin-Starry and Brown-Hopps gram-stained tissues.
• Studies to rule out other common causes of regional adenopathy should be performed.

Imaging Studies

• In patients with disseminated catscratch disease and persistent high fever, abdominal pain, and severe systemic symptoms, an abdominal CT scan can be helpful. Multiple hypodense lesions of the liver and spleen are the major manifestations seen on such scans. These lesions resolve or calcify after weeks to months.

Other Tests

• Bartonella species are fastidious and difficult to culture. They can be isolated in either cell cultures or axenic media with blood-enriched agar plates.
• The catscratch disease skin test is no longer recommended. The test is less sensitive, less specific, poorly standardized, not readily available, not approved by the FDA, and considered by some to be unsafe.

Procedures

• If suppuration occurs, lymph node aspiration may be required. Avoid incision and drainage of nodes because chronic draining sinuses may result.

Histologic Findings

The primary inoculation lesion site consists of acellular areas of necrosis in the dermis with surrounding histiocytes and epithelioid cells. Lymphocytes and multinucleated giant cells can be found surrounding the histiocytes.

Findings in involved lymph nodes can be nonspecific but include lymphoid hyperplasia followed by stellate granulomas. The centers are acellular and necrotic with surrounding histiocytes and lymphocytes. Microabscesses can develop and become confluent at later stages.

Warthin-Starry staining of involved lymph nodes or primary inoculation skin sites may reveal chains, clumps, or clusters of pleomorphic B henselae bacilli.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Most cases require supportive and symptomatic care only. Occasionally, lymph node aspiration is indicated. Antibiotics should not be routinely administered for typical catscratch disease.

Consultations

An infectious disease consultation should be sought in cases of atypical catscratch disease or in cases of catscratch disease in immunocompromised patients.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Analgesics are often used for localized discomfort.

Currently, only limited evidence supports the use of antibiotics in the treatment of typical catscratch disease in the immunocompetent host. B henselae is susceptible to many antibiotics in vitro. However, the susceptibility patterns do not predict efficacy in vivo.

Patients with mild-to-moderate catscratch disease should not receive antibiotics. For patients with extensive symptomatic lymphadenopathy, azithromycin is recommended. All immunocompromised patients with catscratch disease, however, should be treated with antibiotics.

A prospective, randomized, double-blind, placebo-controlled study by Bass et al showed that azithromycin administered for 5 days resulted in decreased lymph node volume as measured by sonography within the first month of treatment. There were no other differences in clinical outcome.

Bartonella is an intracellular bacterium and has poor response to penicillin derivatives in vivo despite susceptibility in vitro.

Musso et al found that aminoglycosides were bactericidal and Ives et al showed that clarithromycin and azithromycin were also efficacious in catscratch disease. Gentamicin, trimethoprim-sulfamethoxazole, rifampin, and ciprofloxacin have also been shown to be reasonable choices for antibiotic therapy.

A single treatment for all Bartonella-related diseases has not been identified, so treatment must be adapted for specific situations.

For retinitis, a combination of doxycycline and rifampin for 4-6 weeks is recommended. For bacillary angiomatosis and peliosis hepatis, long courses of erythromycin or doxycycline are recommended for 3 and 4 months, respectively. In known Bartonella endocarditis, a combination of doxycycline for 6 weeks with gentamicin 3 mg/kg/d IV for 14 days is recommended.

Some patients, usually who are immunocompromised, develop a Jarisch-Herxheimer–like reaction shortly after receiving antibiotic therapy.

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Drug Name	Doxycycline (Doryx, Bio-Tab, Doxy, Periostat, Vibramycin)
Description	Inhibits protein synthesis by binding with the 30S and possibly the 50S ribosomal subunit(s) of susceptible bacteria; may also cause alterations in the cytoplasmic membrane.
Adult Dose	100 mg PO bid
Pediatric Dose	<8 years (<45 kg): Not established >8 years (>45kg): Administer as in adults
Contraindications	Hypersensitivity to doxycycline, tetracycline, or any component of the formulation; children <8 y; severe hepatic dysfunction; pregnancy
Interactions	Antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate decrease bioavailability; can increase hypoprothrombinemic effects of anticoagulants; can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy; CYP3A4 inducers may decrease levels (barbiturates, carbamazepine, phenytoin)
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Do not use during pregnancy -- use of tetracyclines during tooth development may cause permanent discoloration of the teeth and enamel hypoplasia; prolonged use may result in superinfection, including oral or vaginal candidiasis; photosensitivity reaction may occur with this drug; avoid prolonged exposure to sunlight or tanning equipment; avoid in children <8 y

Drug Name	Ciprofloxacin (Cipro)
Description	Inhibits DNA-gyrase in susceptible organisms; inhibits relaxation of supercoiled DNA and promotes breakage of double-stranded DNA.
Adult Dose	500 mg PO bid
Pediatric Dose	<12 years: Not recommended >12 years: 20-30 mg/kg/d PO bid
Contraindications	Documented hypersensitivity to ciprofloxacin, any component of the formulation, or other quinolones
Interactions	Metal cations (aluminum, calcium, iron, magnesium, and zinc) bind quinolones in GI tract and inhibit absorption; may increase theophylline levels; hypoprothrombinemic effect of warfarin may be enhanced by ciprofloxacin; may decrease renal secretion of methotrexate, decrease phenytoin levels, decrease the metabolism of ropivacaine, increase effect of glyburide, and decrease metabolism of caffeine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	CNS stimulation may occur (tremor, restlessness, confusion, and, very rarely, hallucinations or seizures); use with caution in patients with known or suspected CNS disorder; prolonged use may result in superinfection; tendon inflammation and/or rupture have been reported with ciprofloxacin and other quinolone antibiotics; risk may be increased with concurrent corticosteroids, particularly in the elderly; discontinue at first sign of tendon inflammation or pain; adverse effects, including those related to joints and/or surrounding tissues are increased in pediatric patients; rare cases of peripheral neuropathy may occur; severe hypersensitivity reactions, including anaphylaxis, have occurred with quinolone therapy; quinolones may exacerbate myasthenia gravis, use with caution (rare, potentially life-threatening weakness of respiratory muscles may occur); caution in renal impairment; avoid excessive sunlight; may cause moderate-to-severe phototoxicity reactions

Drug Name	Rifampin (Rifadin, Rimactane, Rifadin IV)
Description	Inhibits bacterial RNA synthesis by binding to the beta subunit of DNA-dependent RNA polymerase, blocking RNA transcription
Adult Dose	300 mg PO bid
Pediatric Dose	10 mg/kg/d PO (maximum 600 mg/d)
Contraindications	Documented hypersensitivity to rifampin, any rifamycins, or any component of the formulation; concurrent use of amprenavir, saquinavir/ritonavir (possibly other protease inhibitors)
Interactions	Potent CYP450 inducer with multiple drug-drug interactions; of note, decreases activity of protease inhibitors and nonnucleoside reverse transcriptase inhibitors; effectiveness of oral contraceptives impaired; would evaluate for possible drug interactions when placing a patient on rifampin
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Use with caution and modify dosage in patients with liver impairment; observe for hyperbilirubinemia; discontinue therapy if this in conjunction with clinical symptoms or any signs of significant hepatocellular damage develop; since rifampin has enzyme-inducing properties, porphyria exacerbation is possible; use with caution in patients with porphyria; use with caution in patients receiving concurrent medications associated with hepatotoxicity (particularly with pyrazinamide), or in patients with history of alcoholism (even if ethanol consumption is discontinued during therapy); monitor for compliance and effects including hypersensitivity, thrombocytopenia in patients on intermittent therapy; urine, feces, saliva, sweat, tears, and CSF may be discolored to red/orange; do not administer IV form via IM or SC routes; restart infusion at another site if extravasation occurs; remove soft contact lenses during therapy since permanent staining may occur; regimens of 600 mg once or twice weekly have beenassociatedwith high incidence of adverse reactions including a flulike syndrome

Drug Name	Erythromycin (E.E.S., E-Mycin, Eryc, Erythrocin)
Description	Inhibits RNA-dependent protein synthesis at the chain elongation step; binds to the 50S ribosomal subunit, resulting in blockage of transpeptidation
Adult Dose	500 mg PO qid
Pediatric Dose	Erythromycin ethylsuccinate PO at 40 mg/kg total/d in 4 divided doses (max total daily dose 2 g/d)
Contraindications	Documented hypersensitivity to erythromycin or any component of the formulation; preexisting liver disease (erythromycin estolate); concomitant use with ergot derivatives, pimozide, or cisapride
Interactions	Increases levels of theophylline, warfarin, carbamazepine, cyclosporine, triazolam, alfentanil, bromocriptine, and statin drugs; may increase digoxin levels; serious arrhythmias have occurred with concurrent cisapride use
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Systemic: Use caution if hepatic impairment with or without jaundice has occurred; it may be accompanied by malaise, nausea, vomiting, abdominal colic, and fever; discontinue use if these occur; avoid using erythromycin lactobionate in neonates since formulations may contain benzyl alcohol, which is associated with toxicity in neonates; observe for superinfections; use in infants has been associated with infantile hypertrophic pyloric stenosis (IHPS); macrolides have been associated with rare QT prolongation and ventricular arrhythmias, including torsade de pointes; elderly persons may be at increased risk of adverse events, including hearing loss and/or torsade de pointes when dosage 4 g/d, particularly if concurrent renal/hepatic impairment

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Depending on severity, immunocompromised patients or patients with atypical manifestations of catscratch disease may require hospitalization.

Further Outpatient Care

• Patients should be instructed to return for a follow-up evaluation to ensure resolution of lymphadenopathy in 2-4 months.
• Patients should return to care if their condition worsens or the lymph node starts to suppurate.

Prognosis

• Catscratch disease is usually self-limiting and the prognosis is excellent.
• Complications and sequelae are rare in typical catscratch disease.
• Severe encephalitis and other disseminated forms of B henselae can lead to long-term sequelae.
• The disease very rarely recurs.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Symptoms that do not resolve and persistent lymphadenopathy should be re-evaluated for other infectious etiologies and lymphoma.
• Failure to have the patient follow up for resolution of symptoms and to rule out other etiologies may result in adverse outcomes.
• If antibiotics are administered, monitor for adverse reactions. Dose adjustments may be necessary for children and in cases of renal insufficiency and hepatic disease.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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• Bass JW, Freitas BC, Freitas AD, et al. Prospective randomized double blind placebo-controlled evaluation of azithromycin for treatment of cat-scratch disease. Pediatr Infect Dis J. Jun 1998;17(6):447-52. [Medline].
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Article Last Updated: Aug 15, 2006