Cat Scratch Disease (Cat Scratch Fever) 

Updated: Dec 04, 2018
Author: Stephen J Nervi, MD; Chief Editor: Michael Stuart Bronze, MD 

Overview

Background

Catscratch disease (CSD), also known as catscratch fever or subacute regional lymphadenitis, is a bacterial infection affecting lymph nodes that drain the sites of inoculation. Bartonella henselae, a gram-negative rod, is considered the principal etiologic agent.[1, 2] CSD is one of the most common causes of chronic lymphadenopathy in children and adolescents.

Patients with CSD usually have a history of sustaining a scratch or bite from a cat (typically a kitten). The initial symptom is formation of a papule at the inoculation site, followed by solitary or regional lymphadenopathy within 1-2 weeks (see the images below). In most patients, the disease resolves spontaneously within 2-4 months.

Papulopustular lesions of a primary inoculation si Papulopustular lesions of a primary inoculation site on the hand of a 16-year-old patient. These lesions had been present for approximately 3 weeks. A catscratch antigen skin test was positive with 15-mm induration. No treatment was administered, and her condition resolved spontaneously in 2.5 months. Courtesy of Andrew Margileth, MD.
A crusted primary inoculation papule on the neck o A crusted primary inoculation papule on the neck of a 4-year-old child. Note the adjacent lymphadenitis. This patient had contact with cats and had multiple scratches. Courtesy of Andrew Margileth, MD.
This 13-year-old girl developed fatigue and malais This 13-year-old girl developed fatigue and malaise after being licked and scratched by a cat. The typical conjunctival granuloma was accompanied by a parotid mass and intraparotid adenitis. No treatment was administered, and all her signs and symptoms resolved in 3 months. Courtesy of Andrew Margileth, MD.
This 9-year-old boy developed catscratch disease ( This 9-year-old boy developed catscratch disease (CSD) encephalitis and a papular pruritic dermatitis after sustaining cat scratches and developing regional lymphadenitis. He was in a coma for 4 days but experienced a complete and rapid recovery within 3 weeks. Biopsy of the skin rash revealed nonspecific changes. The CSD antigen skin test result was positive. Courtesy of Andrew Margileth, MD.
This 2.5-year-old boy was recovering from catscrat This 2.5-year-old boy was recovering from catscratch disease acquired 10 months before when he developed this neck abscess over a period of 3 weeks. Biopsy revealed caseating granulomas; acid-fast bacillus and Warthin-Starry stain results were negative. Courtesy of Andrew Margileth, MD.

A small percentage of immunocompetent patients develop severe systemic disease or other atypical manifestations. These may include oculoglandular syndrome, encephalitis, neuroretinitis, pneumonia, osteomyelitis, erythema nodosum, arthralgia, arthritis, and thrombocytopenic purpura.[3, 4, 5, 6, 7, 8, 9, 10]

Infection of immunocompromised patients with the same organism leads to a very different disease, bacillary angiomatosis-peliosis. This disease is characterized by angioproliferative lesions resembling those of Kaposi sarcoma in the skin, liver, spleen, bone, and other organs.

It is necessary to diagnose CSD in a patient with lymphadenopathy to differentiate this benign process from a neoplastic process.[11] However this can be difficult because of limitations to the currently available confirmatory diagnostic tests.[12]

Historical background

The history of CSD has been reviewed comprehensively by Carithers[13] in 1970 and by Margileth[14] in 1987. It is summarized here.

Henri Parinaud sometimes is given credit for the first description of CSD in 1889.[15] However, the oculoglandular syndrome of conjunctivitis with an enlarged preauricular lymph node that he reported ultimately was shown to comprise only a small subset of the possible clinical presentations of CSD, the result of inoculation of the CSD agent into the conjunctivae. Parinaud did not make the association with cat exposure; thus, his contribution is of limited scope.

In 1931, Dr. Robert Debré and his colleague Georges Semelaigne observed an unusual case of suppurating epitrochlear adenitis in a 10-year-old boy at the University of Paris and noted a number of cat scratches on the affected side. These were believed to be portals of entry for tubercle bacilli. When the tuberculin skin test results turned out to be negative, the investigators pursued an infectious cause of feline origin.

While bacteriologic investigations yielded no clues, the physicians continued to observe similar cases of spontaneously remitting regional lymphadenitis associated with cat scratches in their pediatric population. Debre postulated tularemia, pasteurellosis, infectious mononucleosis, or tuberculosis as possible etiologic agents, but with no convincing proof.

Foshay, a microbiologist at the University of Cincinnati, suspected CSD to be a possible manifestation of tularemia. On meeting Debre in 1947, the 2 investigators compared notes on "catscratch disease" (Debre) and "cat fever" (Foshay). Foshay had produced an antigen from the pus of affected patients and achieved what was believed to be a diagnostic reaction after intradermal injection. Debre and his colleagues subsequently developed a similar antigen and demonstrated reactions in both old and new cases of CSD.

These results were presented and published in 1950.[16] These investigators also recorded failure of transmission of CSD to 15 different species of animals and possible human-to-human transmission in 1 of 4 cases.

In 1951, Greer and Keefer published the first report of CSD in American literature, in which they described a broader spectrum of CSD manifestations.[17] In the late 1950s, William Warwick of the University of Minnesota collaborated with Robert Good in an attempt to transmit CSD to "every variety of lab animal from the monkey to the mouse." Their only positive result was the development of cutaneous lymphadenopathy in a monkey given intracerebral injections of ground lymph nodes and pus.

In 1967, Carithers published the first thorough review of the world's literature on CSD, which included 567 references and detailed the manifold clinical presentations. This landmark publication of a series of 1200 cases evaluated by a single observer put the varied clinical presentations into perspective and provided the first realistic analysis of the spectrum of disease.[3]

Discovery and classification of the etiologic agent for CSD is one of the triumphs of modern microbiology. The elegance and power of molecular taxonomy applied to the CSD agent revealed unexpected connections with other well-recognized infectious diseases and a deeper understanding of the pathogenesis of CSD.

Both viruses and Chlamydia had been proposed as possible etiologic agents for CSD, until a small gram-negative motile coccobacillus was observed in infected lymphatic tissue using a Warthin-Starry stain and Brown-Hopp tissue Gram stain in 1983 at the Armed Forces Institute of Pathology.[18] In 1984, Margileth et al, using the same staining technique, demonstrated identical organisms in biopsy specimens taken from CSD inoculation papules.[19]

The first successful isolation and culture of the CSD organism was performed by English et al in 1988.[20] Their further studies fulfilled Koch's postulates, and the organism was determined to be the cause of CSD.

One of the isolates from the study by English et al was investigated at the US Centers for Disease Control and Prevention, along with additional specimens from Tripler Army Medical Center in Honolulu. From these specimens, the CSD organism was determined to be a new entity and given the name Afipia (from Armed Forces Institute of Pathology) felis.

Reports associating another agent (Rochalimaea henselae) with CSD began appearing in 1992. Although they are not closely related, R henselae and A felis are both members of the alpha-2 subclass of Proteobacteria and share a similar microscopic appearance and affinity for the Warthin-Starry stain.

R henselae already had been implicated in the pathogenesis of bacillary angiomatosis, an angioproliferative condition observed in patients who are immunocompromised. Reports of R henselae –associated CSD appeared, and new immunological data subsequently supported a major role for R henselae as the etiologic agent in CSD. Although R henselae now is believed to be the principal pathogen in CSD, both organisms have been reported in some patients with CSD.[21]

When the sequences of 16S bacterial rRNA from R henselae and Bartonella were compared, these organisms were determined to be so clearly closely related that they belonged in the same genus. Because Bartonella had historical precedence, R henselae was renamed Bartonella henselae.

A Medscape General Medicine article that may be of interest is " Do Bartonella Infections Cause Agitation, Panic Disorder, and Treatment-Resistant Depression? "

Pathophysiology

Most cases of CSD are caused by Bartonella henselae.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.[22]

The hallmark of CSD 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 to Bartonella infection can be vasculoproliferative with neovascularization. Bartonella is able to promote angioproliferation through adhesin A, which is observed in bacillary angiomatosis, peliosis, and verruga peruana.

Nine outer membrane proteins (OMP) of B henselae have been identified. The 43-kD OMP is a major protein capable of binding endothelial cells; further investigation is needed to clarify its role in the pathogenesis of CSD.

Feline infection with B henselae is common and asymptomatic. In the United States, 28% of surveyed cats had antibodies against the organism. In California, blood cultures were positive in 56% of domestic cats younger than 1 year and in 34% of cats older than 1 year. More than three fourths of all cats in California had antibodies to B henselae as evidence of prior infection; however, only 21% of pet cats were bacteremic, compared with 61% of stray cats.

A similar survey of cats in the Baltimore area found seropositivity in 12-14% of domestic cats versus 44% of feral animals. Cats can be asymptomatically bacteremic for months, even while antibody titers are developing.

The organism has been isolated from fleas residing on infected cats. Studies have shown that flea-vectored transmission of infection among cats occurs with high efficiency and that in the absence of fleas, infected cats do not transmit the infection to uninfected cats.

Although flea-vectored transmission to humans has not been documented, it could explain some cases in which the patient has no history of exposure to cats. Treatment of cats with doxycycline is associated with a reduction of bacteremia, but whether such treatment prevents relapse or reinfection is unknown.

Familial and household clustering of cases of CSD have been reported. However, only one member of a family in contact with an infected cat usually is affected.

Zangwill et al[23] found an 18% prevalence rate of seropositivity to B henselae among family members of patients with CSD. Upon further questioning, 43% of these individuals reported symptoms consistent with CSD during the previous 2 months. In the same study, matched control subjects not exposed to cats exhibited a 3.6% seropositivity rate. Carithers found similar results in a series of 1200 patients; 18.5% of asymptomatic family members had positive CSD antigen skin test results.[3]

Many organ systems are affected by CSD, including the lymph nodes, CNS, eyes (neuroretinitis), skin (bacillary angiomatosis, erythema nodosum, erythema multiforme), lungs, and bones (arthritis and osteomyelitis).

Lymph nodes

In general, lymph nodes become enlarged in the 1-2 weeks after exposure. They are often tender and occasionally become fluctuant.

Lymphoid hyperplasia with arteriolar proliferation and reticular cell hyperplasia is seen early in the disease. As the disease progresses, granulomas appear, with central necrosis surrounded by lymphocytes. Histiocytes and multinucleated giant cells are often present. Finally, stellate microabscesses form, and nodes can become fluctuant.

Central nervous system

Encephalopathy is the most common neurologic manifestation, occurring in 2-3% of patients. This complication may be more common in adults than in children. The onset is usually abrupt and occurs 1-6 weeks after the lymphadenopathy becomes apparent.

Patients can become confused and disoriented, and their condition can deteriorate to coma. About 50% of patients have a fever. Focal findings of hemiparesis and reflex abnormalities may be noted. Seizures, which occur in as many as 80% of patients with neurologic sequelae, are often prolonged and recurrent.

The pathogenesis of encephalopathy is unknown, but it is not likely due to direct infection, because CSF is usually normal and recovery is rapid, often without antibiotic therapy. CT scans are often normal, and CSF examination shows mononuclear pleocytosis in 20-30% of patients. Electroencephalographs (EEGs) show nonspecific slowing. Recovery is usually complete in a 1 week or longer, but persistent neurologic deficits have been reported.

Neuroretinitis

Patients with neuroretinitis generally present with painless, unilateral visual loss. Examination reveals decreased visual acuity, decreased color vision, and centrocecal scotoma. The optic disc appears edematous, and exudates frequently surround the macula.

Neuroretinitis is possibly due to a subretinal angiomatous nodule similar to that seen in bacillary angiomatosis.

Bacillary angiomatosis

Bacillary angiomatosis almost exclusively occurs in patients who are immunocompromised. Skin lesions consisting of numerous brown to violaceous or colorless vascular tumors of the skin and the subcutaneous tissue are the most common manifestation. Disseminated disease may involve bone, liver, spleen, lymph nodes, the gastrointestinal and respiratory tracts, and bone marrow.

B henselae and Bartonella quintana have been isolated from samples of cutaneous and osseous bacillary angiomatosis lesions. Histologic examination with Warthin-Starry staining reveals vascular proliferation with numerous bacillary organisms.

Pulmonary

Six cases of CSD with pneumonia and 8 cases with pleural thickening and/or effusion have been reported. In these cases, pulmonary features developed 1-5 weeks after lymphadenopathy occurred. Systemic signs of infection, including fever, were present in 85%. One case in which a massive abscess involved the chest wall has been reported.

Vertebral osteomyelitis and splenic abscess

Rolain et al have described vertebral osteomyelitis with splenic abscess in a patient with CSD.[24] B henselae was specifically identified as the etiological agent using several direct and indirect methods, including histologic and serologic assays, as well as immunofluorescent detection on slide appositions using a monoclonal antibody. This represents the second case of osteomyelitis associated with CSD.

Etiology

Catscratch disease is usually caused by B henselae, formerly known as Rochalimaea henselae. B henselae is a small, fastidious, slow-growing, gram-negative, aerobic, nonmotile, pleomorphic bacillus. In the genus Bartonella, B bacilliformis, B quintana, B elizabethae, B vinsonii, and B koehlerae are also responsible for human disease. B clarridgeiae, has rarely been associated with cases of CSD.

Studies have demonstrated B henselae seropositivity rates ranging from 3.1-61.6% in the general population, depending on the country in which the study was performed. In all instances, few patients ever experienced symptoms, suggesting that only a minority of exposures to B henselae result in CSD.

Domestic cats are the natural reservoir and vectors of B henselae. In cats, B henselae infection is asymptomatic. Fleas are believed to transmit the bacteria between cats, and seroprevalence in cats is highest in warm or humid climates, where prevalence of flea infestation among cats is higher.

The transmission of B henselae from cats to humans occurs via a scratch or bite when the bacterium is present on the cat’s claws or oral cavity. More than 90% of patients with CSD have a recent history of contact with a cat, usually a kitten, and about 75% of these patients give a history of cat scratch or bite. Dogs have been implicated in 5% of cases.[25, 26] Occasional cases of infection associated with monkey bites have also been reported.

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 are more likely to scratch. Individuals who have been scratched or bitten by a kitten are 27 times more likely to become infected, and people who have at least one kitten with fleas are 29 times more likely to become infected than people whose animals were free of fleas.

In approximately 1% of diagnosed cases, no animal scratch is implicated. Person-to-person transmission has not been documented. No evidence exists to suggest transmission from cat fleas to humans. Ticks and biting flies have also recently been recognized as potential vectors.[27] Cases occurring after scratches from thorns, wood splinters, and crab claws have occurred. However, in each of these cases, the patient recalled that a cat licked the abrasion.

Familial outbreaks have been documented and have usually involved siblings, or in rare instances parents. Symptoms among siblings often appear within 3 weeks of the index case.

A rare report describes veterinarian who developed fever of unknown origin and persistent backache a month after an accidental needle puncture. Serology and molecular identification confirmed it to be B henselae infection.[28]

Epidemiology

United States statistics

A limited survey performed in 1993 by the Centers for Disease Control and Prevention reported approximately 22,000 cases of catscratch disease (CSD) diagnosed annually, although many additional cases are likely unrecognized.[29] More than 2,000 hospital admissions with a discharge diagnosis of CSD are reported annually.[29] The estimated incidence among ambulatory patients is approximately 9.3 cases per 100,000 persons per year.[29] In 2000, approximately 437 pediatric hospitalizations associated with CSD were reported.[30]

Cases of CSD occur throughout the United States. The incidence is greater in regions with higher temperatures and humidity (eg, Hawaii, Pacific Northwest, southeastern states, coastal California), while Alaska, the Rocky Mountains, and midwestern states have a prevalence lower than the median. Only 1 genotype of B henselae has been reported in North America.

Approximately 70-90% of CSD cases occur in the fall and early winter months. This seasonality is presumed to be due to a midsummer rise in kitten births accompanied by increased flea infestation.

Reynolds et al found that the CSD-associated hospitalization rate in the United States was 0.60 per 100,000 patients younger than 18 years and 0.86 per 100,000 patients younger than 5 years.[30] The median hospitalization charge for catscratch disease has been estimated to be $46,140, and annual expenses are estimated to be about $3.5 million.

International statistics

CSD disease has been reported worldwide; however, the international incidence is unknown. Seroprevalence rates vary greatly throughout the world, ranging from 0.6-37% and reflecting cat populations in each country. The disease is more prevalent in areas with warm humid climates.

In temperate climates, catscratch disease predominantly occurs in autumn and winter; in the tropics, seasonal changes in frequency of the disease are not observed. Sanguinetti-Morelli et al (2011) found that in France, most cases of CSD occurred from September to April, with a peak in April.[31]

At least 2 genotypes of B henselae have been isolated from cats in Europe. B henselae is endemic in Europe, Africa, Australia, and Japan. In Germany, B henselae was the causative agent of head and neck lymphadenopathy in 61 (13.4%) of 454 patients[32] and the most common cause of lymphadenopathy in adults and children.[32, 11]

Sexual differences in incidence

In some case series, CSD occurs more frequently in males than females (male-to-female ratio of 3:2), while others show equal rates between males and females. One hypothesis to explain a greater incidence among males is the tendency toward rougher play with kittens and cats and consequently an increased risk of bites and scratches.

Age-related differences in incidence

In a database analysis by Jackson et al, 55% of patients with CSD were 18 years of age or younger.[29] Older literature suggests that more than 80% of cases occur in persons younger than 21 years.

The younger age of individuals most likely to acquire CSD reflects their likelihood of exposure to the major risk factor (ie, kittens). On the other hand, a bias may exist in the literature because pediatricians have collected many of the large case series.

Patients older than 60 years are more likely to present with atypical features of catscratch disease. Especially in adults older than 49 years of age, CSD can occur concurrently with neoplasm and mycobacteriosis.[11]

Prognosis

The prognosis for immunocompetent patients with CSD is excellent. Complete recovery without sequelae occurs in nearly all patients. Significant morbidity occurs in 5-10% of cases, usually because of involvement of the central or peripheral nervous system or because of multisystem disseminated disease. Even in patients with CNS involvement, however, recovery without neurologic sequelae within weeks to months can be expected. Death caused by CSD in patients who are immunocompetent is extremely rare.[33, 34] )

Lymphadenitis usually resolves spontaneously over 2-4 months, but 1-2 years may be required. One episode of catscratch disease confers lifelong immunity to children and adolescents. Recurrent lymphadenopathy 6-13 months after the initial diagnosis has been reported in 3 adults with CSD.

Immunocompromised patients may experience a dramatic and potentially life-threatening course of disease. However, with appropriate antibiotic use and management of complications, these patients also typically experience full resolution of disease.

Patient Education

Assure parents that the disease will resolve spontaneously and that an episode of CSD confers long-term immunity. Although rare, adults can have recurrent illnesses.

Teaching children how to handle pets gently and declawing pets may decrease the incidence of CSD. The animal is infectious for only a short period, so removal of the pet from the home is not recommended. Advise patients and caregivers to control fleas on kittens to prevent spread of B henselae infection among animals.

 

Presentation

History

Patients with catscratch disease (CSD) most often seek medical care because of tender regional lymphadenopathy, typically involving axillary, cervical, submandibular, or preauricular nodes.

Most patients with CSD report a history of exposure to cats, and especially kittens. When questioned, patients may recall being scratched, licked, or bitten by a cat in the previous 2-8 weeks. Transmission can occur by petting alone with subsequent self-inoculation via a mucous membrane, skin break, or conjunctiva. However, infection with B henselae can be transmitted by arthropod vectors, and a history of an animal scratch or bite is not necessary for disease transmission.[35]

More than 90% of patients with CSD develop one or more 3- to 5-mm red-brown nontender papules at the site of inoculation 3-10 days after the bacteria are introduced. These primary lesions last for 1-3 weeks then recede as lymphadenopathy appears.

Within 1-3 weeks, lymphadenopathy develops in a single node or group of regional nodes draining the inoculation site. Single node involvement occurs in more than one half of patients. More than 65% of cases involve the nodes in the axillae or anterior or posterior triangles of the neck. Inguinal lymphadenopathy has been reported in 17% of cases.

Lymphadenopathy can be moderately tender, with erythema and increased warmth of the overlying skin. Lymphadenopathy remains regional and typically resolves within 2-4 months but may last up to 6-12 months. Rarely, it may persist for a year or more. Approximately 10-30% of nodes may suppurate, requiring needle aspiration.

Approximately 50% of patients also experience systemic symptoms. These might include the following (see also Table 1, below):

  • Malaise/fatigue (29.4%)

  • Fever (28%)

  • Anorexia (14.5%)

  • Headache (13%)

  • Sore throat (7%)

  • Arthralgia (2.5%)

CNS findings are present in 5% of patients with CSD. In addition to headaches, these may include mental status changes, seizures, myelitis, transient peripheral neuropathy, and retinitis. The presence of abdominal pain with a history consistent with CSD suggests CSD hepatitis/splenitis, a self-limited granulomatous condition.

Table 1. Clinical Manifestations of CSD [4] (Open Table in a new window)

Sign or Symptom

Percentage, %

Average Duration, d

Adenopathy

100

14-180

Adenopathy only

52

14-180

Inoculation site

59-93

7

Fever >101°F (38.3°C)

32-60

6

Malaise/fatigue

29

13

Headache

13

4

Anorexia, weight loss, emesis

14

5

Splenomegaly

12

11

Sore throat

5

2

Rash

5

8.5

Parotid swelling

2

-

Conjunctivitis

4.5

-

Margileth et al studied a series of 1312 patients referred for chronic lymphadenopathy. The diagnosis of CSD was confirmed in 1174 patients via catscratch antigen (CSA) testing, similar to the tuberculosis purified protein derivative (PPD) test. Of this cohort, 88% exhibited a typical course characterized by lymphadenopathy lasting an average of 3 months. Fever and malaise/fatigue were described in approximately one third of patients, none of whom was symptomatic for longer than 1 month.

An unusual presentation was experienced by 11.6% of the cohort. Of these, Parinaud oculoglandular syndrome (POS) was found in half the patients, followed in decreasing order of frequency by encephalopathy (2.3%), systemic disease (2%), erythema nodosum (0.6%), atypical pneumonia (0.2%), breast tumor (0.2%), and thrombocytopenic purpura (0.1%).

A subset of patients with severe systemic disease was observed for 7 years.

Differences between the group with severe disease and those patients with typical CSD included more frequent primary skin or mucous membrane lesions, fewer animal contacts and cat scratches, greater frequency and duration of fevers, and other constitutional symptoms.

Skin eruptions (eg, urticaria, vesiculopapular lesions, erythema nodosum) occurred 4 times more often in the severe CSD group compared with the typical CSD group. Demographics of the severe disease group included a greater percentage of adult males, who tended to have larger and multiple affected lymph nodes. Fortunately, all patients fully recovered. The longest period of recuperation was 4.5 years.

Another interesting finding from this series was evidence of recurrent CSD. Three of the patients in the severe disease category experienced recurrences at 4- to 20-month intervals. One patient presented with recurrent cervical lymphadenitis, whereas the other 2 patients experienced systemic symptoms with periodic fever, malaise, headache, and weight loss. In one patient, the episodes lasted 1-3 months, with a 20-month interval, while the second patient experienced similar episodes with a 10-month interval.

Physical Examination

In 1-3 weeks, the inoculum-site lesion evolves from a small, 2- to 5-mm reddish-brown macule or vesicle to a papule or pustule (see the images below). Often, it is mistaken for an insect bite. Lesions typically are nonpruritic and heal in days to months without scarring.

Papulopustular lesions of a primary inoculation si Papulopustular lesions of a primary inoculation site on the hand of a 16-year-old patient. These lesions had been present for approximately 3 weeks. A catscratch antigen skin test was positive with 15-mm induration. No treatment was administered, and her condition resolved spontaneously in 2.5 months. Courtesy of Andrew Margileth, MD.
A crusted primary inoculation papule on the neck o A crusted primary inoculation papule on the neck of a 4-year-old child. Note the adjacent lymphadenitis. This patient had contact with cats and had multiple scratches. Courtesy of Andrew Margileth, MD.

Careful examination may reveal an inoculation papule in the majority of patients. Given the tendency to hold cats against one's chest, the lesion is found most often on the head or upper extremities. Include the scalp, finger web spaces, eyelids, and conjunctiva in a thorough inspection. Multiple sites may be infected.

A transitory rash may occur early in the course of the disease. Most commonly, the rash is an evanescent maculopapular rash.

One or more nodes draining the site of inoculation enlarge approximately 2 weeks (range 5-50 d) after contact with the kitten or cat. The overlying skin may be warm and erythematous, but only rarely is an associated cellulitis present. (See the image below.)

This 10-year-old child had contact with dogs but n This 10-year-old child had contact with dogs but not cats. The impressive lymphadenitis had been present for 5 weeks and was not tender. Pathologic examination of a biopsy specimen of the lymph node revealed nonspecific changes. She had a positive catscratch disease skin test result and negative purified protein derivative skin test results. Treatment with cephalexin was administered with a good response. Complete resolution occurred in 4.5 months. Courtesy of Andrew Margileth, MD.

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, or occasionally larger. Lymphadenitis resolves over 2-4 months, rarely persisting longer than a year.

Suppuration of the involved nodes occurs in 8.5-30% of patients. The risk of suppuration is proportionate to the size of the lymphadenopathy. Nodes that drain may heal with scarring.

Conjunctival CSD may manifest as nonsuppurative conjunctivitis or ocular granuloma.

Fever, if present, is typically low grade. In one series of 1200 cases of catscratch disease, only 9% of patients had a fever higher than 39°C. Fever is present in only 30-50% of patients and generally lasts for 1-7 days. About 32% of patients have prolonged fever, or one lasting up to 3 weeks. Such fever suggests progression to suppurative lymphadenitis.

CSD may present as fever of unknown origin. In a series of prolonged fever without a source, CSD was one of the most common diagnoses.[36] Adenopathy may not be present. Abdominal pain may be the initial finding, along with fever, in hepatosplenic CSD disease.

Malaise, fatigue, and other constitutional symptoms occur in up to 30% of patients. Headache, sore throat, and anorexia are noted in approximately 13% of patients.

A report from Canada describes CSD presenting as acute mastoiditis in a 6-year-old girl.[37]

Less common symptoms are splenomegaly (11%), exanthems (4.5%), conjunctivitis (4.3%), and parotid swelling (1.4%). Although erythema nodosum, erythema marginatum, erythema multiforme, and erythema annulare have been associated with CSD, exanthems consist of a truncal maculopapular rash.

Atypical Catscratch Disease

Other problems (ie, atypical CSD) occur in approximately 10% of cases. Atypical manifestations of CSD include the following (see also Table 2, below):

  • Parinaud oculoglandular syndrome

  • Central nervous system (CNS) involvement

  • Hepatosplenic CSD

  • Endocarditis

  • Osteomyelitis

  • Joint pain (arthritis, synovitis)

  • Respiratory complaints (atypical pneumonitis)

  • Dermatologic manifestations

Table 2. Clinical Manifestations of Atypical CSD [14, 3] (Open Table in a new window)

Clinical Feature

Margileth,

n = 1174, %

Carithers,

n = 1200, %

Typical presentation

88.4

95

Inoculation lesion (skin, eye, mucous membrane)

58.6

 

Unusual presentation

11.6

5

Parinaud oculoglandular syndrome

6.3

4

Encephalopathy

2.3

0.25

Systemic disease, severe, chronic

2

 

Erythema nodosum

0.6

0.42

Atypical pneumonia

0.2

 

Breast tumor

0.2

 

Thrombocytopenic purpura

0.1

0.08

Parinaud oculoglandular syndrome

Parinaud oculoglandular syndrome, which is characterized by unilateral conjunctivitis with adjacent preauricular lymphadenopathy, occurs in 2-3% of patients with CSD.[38] In these patients, the site of inoculation is usually the eyelid or conjunctiva secondary to a lick, scratch, or bite.

Subsequent rubbing of the eye often leads to spreading. After a few weeks, the patient develops nonpurulent conjunctivitis, an ocular granuloma, or both. Preauricular adenopathy also develops. Physical findings involving the eye resolve in a few months without residual damage.

Examination of the palpebral conjunctiva on the involved side reveals either a characteristic granulomatous lesion 2-4 mm in diameter or a frank scratch. While POS has been associated with other infections (eg, tuberculosis, tularemia, lymphogranuloma venereum), it most commonly is associated with CSD. Prognosis is identical to that of typical CSD.

Central nervous system involvement

CNS findings occur in 5% of patients with CSD and include encephalitis, seizures, myelitis, peripheral neuropathy, and neuroretinitis.

Encephalopathy is a complication of CSD described in up to 5% of patients Although encephalitis usually follows development of lymphadenopathy by 1-6 weeks, it may precede or occur without the presence of lymph node involvement.[39, 40, 41, 42] Most patients are young, in parallel to the spectrum of patients diagnosed with CSD.

Encephalitis occurs in approximately 2-4% of CSD cases; the condition is characterized by confusion, restlessness, combativeness, and disorientation. Generalized headache and transient nuchal rigidity are often present. Symptoms rapidly progress within hours to seizures and coma.[43] Seizures occur in one half to three fourths of patients and may be self-limited or progress to status epilepticus. Coma complicated by respiratory depression requiring intubation and ventilatory assistance often is reported.

Laboratory findings from examination of cerebrospinal fluid (CSF) often are normal. Even when CSF results are abnormal, no consistent patterns emerge. Abnormal findings from EEG, when observed, are nonspecific and transient. CT or MRI study findings of the brain are usually normal or reveal transient abnormalities.

CSD encephalitis is self-limited, does not mandate specific treatment, and rarely results in persistent impairment. Recovery is usually complete in 2-10 days, with no sequelae. However, persistent cognitive impairment and death have been reported in some cases.

Transverse myelitis presenting as Brown-Sequard syndrome has occurred in a 44-year-old man.[44] Myelitis presented with extremity weakness, abnormal reflexes, sensory loss, and sphincter dysfunction. The patient experienced rapid resolution of symptoms in a few days and was asymptomatic within 3 months.

Cranial or peripheral nerve involvement may occur. Two children with oculoglandular CSD were reported to have developed transient facial nerve paresis. Three adult women reportedly developed peripheral neuritis lasting 1-4 months associated with the onset of lymphadenitis due to CSD.

Acute onset, self-resolving, recurrent expressive aphasia has been reported.

Neuroretinitis (Leber stellate neuroretinitis, Leber idiopathic stellate retinopathy,[45] Leber idiopathic stellate maculopathy) was first described in 1916. It often follows lymphadenopathy or an influenzalike syndrome. Patients present with painless, unilateral (rarely bilateral) decreased vision associated with central scotomata. Funduscopic examination reveals papilledema with macular exudates in a star pattern.

Permanent loss of vision is not reported, although recovery may take 1-3 months. CSD neuroretinitis should be followed by an ophthalmologist but is predictably self-limited.

Recovery from CNS manifestations of CSD may be slow. Some individuals require one year or longer to recover from CNS manifestations.

Hepatosplenic catscratch disease

Hepatosplenic CSD is a rare form of atypical CSD found in patients who are immunocompetent. Individuals present with daily fevers up to 104°F (40°C) and no identifiable cause.

Physical examination findings are usually normal, with occasional detection of well-healed cutaneous scars secondary to cat scratches. Abdominal discomfort, without focal findings, is commonly reported. Lymphadenopathy is present in approximately half the cases. Hepatosplenomegaly, jaundice, and elevated transaminase levels are not associated with this condition.

The diagnosis is based on characteristic filling defects in the liver, spleen, or both as detected by ultrasonography, CT scanning, and a positive B henselae titer. The liver is described as having a nutmeg appearance with stellate necrotizing granulomata on the histologic examination.

Intravenous administration of aminoglycoside antibiotics has been reported to be helpful. Most patients become afebrile within 48 hours of initiating treatment; however, in a few cases, fever has persisted for up to a month, even with antibiotic therapy.

Endocarditis

Bartonella species account for approximately 3% of all cases of endocarditis. Currently, many cases of blood culture–negative endocarditis are believed to be the result of infection with Bartonella species. Bartonella endocarditis should be considered in patients with manifestations of endocarditis and negative blood culture results who have regular contact with cats.[46] Possible risk factors include alcoholism, homelessness, and body louse infestation.

Some cases diagnosed as Chlamydia endocarditis also are likely to be caused by Bartonella species because of the high prevalence of cross-reacting antibodies.

Patients with Bartonella endocarditis often require valve replacement.

Musculoskeletal involvement

Osteomyelitis secondary to B henselae, while still rare, is being reported with increased frequency. Hajjaji et al reviewed the literature and found 47 cases that met criteria and had sufficient data.[47] They noted the vertebral column and pelvic girdle were the most commonly affected locations.

MRI, scintigraphy, and CT scanning can all be used to demonstrate bone involvement. Immunosuppression was not a risk factor. Affected patients responded well to therapy without significant long-term effects. In a case report, a child with osteomyelitis and epidural extension confirmed by polymerase chain reaction responded to intravenous clindamycin and gentamicin.[48]

A few patients with CSD have been described with osteolytic lesions but not true osteomyelitis. These patients do not have a fever or leukocytosis.

Back pain as the presenting symptom has been reported. In one case report, CT scanning revealed a soft-tissue mass dorsal to the processi transversa L1-2, and MRI revealed a contrast-enhancing paraspinal mass with infiltration of the erector spinae consistent with inflammation.[49] B henselae immunoglobulin (Ig)M antibody findings were positive. The patient spontaneously recovered after about 1 month.

Dermatologic manifestations

Other dermatologic manifestations occur in approximately 5% of patients and are more likely to occur in patients with more severe or atypical disease. These manifestations include macular, maculopapular, morbilliform, and petechial rashes. They typically are nonpruritic and resolve in days to weeks. Cases of erythema multiforme, erythema nodosum, erythema annulare, and ecchymoses associated with thrombocytopenia have been reported in patients with CSD, but these are rare.

Characterized by painful, tender, subcutaneous nodules on the skin, erythema nodosum may present 1-6 weeks after onset of adenopathy in less than 1% of patients with CSD. These nodules resolve without sequelae.

Thrombocytopenia purpura is quite rare and is usually transient.

Immunocompromised Patients

Patients with HIV infection have an increased risk of CSD. The inoculation sites may be difficult to distinguish from Kaposi sarcoma. The normally benign disease of CSD can be life-threatening to an immunocompromised host. These patients, as well as other immunocompromised patients (eg, those with cancer, persons who have undergone transplantation) may develop bacillary angiomatosis, bacillary peliosis, or persistent or relapsing fever with bacteremia.

Bacillary angiomatosis is a vasculoproliferative disease that mostly involves the skin but can involve 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 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 may result in blood-filled spaces in the liver.

 

DDx

Diagnostic Considerations

Consider all causes of subacute and chronic lymphadenopathy. However, infection with cytomegalovirus, human immunodeficiency virus type 1, or Epstein-Barr virus usually is associated with lymphadenitis at more than one site. In patients with persistent skin papules and regional lymphadenopathy, consider leishmaniasis, Nocardiosis, and fungal infections.

Because the clinical manifestations of infection with Bartonella henselae are different in patients who are immunocompromised, an entirely different differential diagnosis is appropriate. Bartonella infection leads to vasculoproliferative lesions, namely bacillary angiomatosis (B henselae, Bartonella quintana) and peliosis (B henselae only). The differential diagnosis includes malignant neoplasms (eg, Kaposi sarcoma, angiosarcoma) and benign reactive conditions (eg, pyogenic granuloma, angiolymphoid hyperplasia with eosinophilia).

Differential Diagnoses

 

Workup

Approach Considerations

Consider all causes of subacute and chronic lymphadenopathy. However, infection with cytomegalovirus, human immunodeficiency virus type 1, or Epstein-Barr virus usually is associated with lymphadenitis at more than one site. In patients with persistent skin papules and regional lymphadenopathy, consider leishmaniasis, Nocardiosis, and fungal infections.

Because the clinical manifestations of infection with Bartonella henselae are different in patients who are immunocompromised, an entirely different differential diagnosis is appropriate. Bartonella infection leads to vasculoproliferative lesions, namely bacillary angiomatosis (B henselae, Bartonella quintana) and peliosis (B henselae only). The differential diagnosis includes malignant neoplasms (eg, Kaposi sarcoma, angiosarcoma) and benign reactive conditions (eg, pyogenic granuloma, angiolymphoid hyperplasia with eosinophilia).

Serologic Testing

Indirect fluorescence assay (IFA) testing and Enzyme-linked immunoassay (ELISA) are used to detect serum antibody to B henselae. An antibody titer that exceeds 1:64 suggests recent Bartonella infection. Paired acute and convalescent sera (drawn 6 wk apart) showing a 4-fold 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.

IFA testing for Bartonella is quite variable, as many different tests are available; test sensitivity may be as low as 53% but is up to 100% in some series, with a specificity of 98%. About 84% of patients have positive titers within 1-2 weeks of clinical CSD, and 16% develop positive titers 4-8 weeks later.

Accuracy of IFA can be improved by concurrent use of both immunoglobulin G (IgG) and immunoglobulin M (IgM) testing.[50] Specificity of IgM and IgG testing ranges from 88-98% and 50-62%, respectively. Most populations have low (2-6%) background seropositivity rates, limiting false-positive test results. The IFA shows cross-reactivity between Bartonella species, Epstein-Barr virus, cytomegalovirus, Toxoplasma gondii, and Streptococcus pyogenes.[51]

ELISA testing for IgM has a sensitivity of 95% and a specificity of 77%. ELISA for IgG has a sensitivity of only 18%. Genotypic and phenotypic differences between B henselae strains are widely encountered and lead to antigenic variation and difficulty in interpreting the results of serologic tests.

A standard pattern of anti-B henselae IgG and IgM production does not seem to exist. Some patients with CSD have high levels of both IgG and IgM, some have high levels of only IgM, and others have low levels of both. The timing of IgG and IgM response is variable, and cross-reactivity between different Bartonella species may occur. In one study, 25% of patients remained IgG seropositive for longer than 1 year. Antibody kinetics do not reliably predict severity or duration of disease.

The prevalence of seropositivity in cats living in the same house as a human with CSD is 81%, versus 14-44% in unselected households.

Biopsy

Lymph node biopsy generally is not indicated in typical cases of CSD, given the associated morbidity and expense. Node aspiration in patients suspected of having CSD traditionally has been discouraged for fear of fistula formation. Consider performing a biopsy of an affected lymph node or skin in cases of possible malignancy or in an unclear presentation in an immunocompromised host. Ultrasonography may be performed to determine if a lymph node is fluctuant and amenable to needle aspiration.

PCR of a biopsy specimen is the most sensitive test and is able to differentiate between different Bartonella species, as well as subspecies and strains. However, this test is not readily available. A presumptive diagnosis of infection with CSD bacilli can be made with Warthin-Starry and Brown-Hopps gram-stained tissues. Immunostaining with BhmAB has been reported to be a better alternative than Warthin-Starry stain in demonstrating the organism.[52]

The sensitivity of PCR with samples of lymph node tissue or aspirates is 30-60% for CSD. If histologic and serologic tests are coupled with PCR analysis, the sensitivity increases to 87%. A 2-step approach (initial testing by PCR/citrate synthase (CS) assay followed by PCR/rRNA assay for PCR/CS-negative specimens) has been suggested for patients in whom CSD is strongly suspected.[12] PCR assays are available in some research and commercial laboratories.

Histopathological findings on biopsy depend on when in the course of the disease the biopsy is performed. Early findings include lymphoid and reticular cell hyperplasia and arteriolar proliferation. Later, granulomas with central necrosis often appear along with multinucleated giant cells. Microabscesses appear later.

Histopathological features of lymph nodes are consistent but not pathognomonic for CSD. Features include granuloma formation, stellate abscesses, and lymphocytic infiltrates. Brown-Hopp tissue Gram stain and Warthin-Starry silver staining can show clumps of small, curved, gram-negative bacilli (shown in the image below). These are usually found in the walls of blood vessels and in the microabscesses and macrophages that line the sinuses.

Warthin-Starry stained sections of lymph node show Warthin-Starry stained sections of lymph node showing chains and clusters of organisms. Courtesy of Andrew Margileth, MD.

Culturing Bartonella species is difficult, as the ideal medium has not been established. Blood agar is often used, and incubation for up to 6 weeks is frequently necessary. Results are often negative.

Skin biopsy of the inoculation papule may be diagnostic. In patients with hepatosplenic CSD, liver and spleen biopsies may also show granulomas and abscesses.

Skin Testing

The CSD skin test is no longer recommended. The test is less sensitive and specific than serologic testing, poorly standardized, and not approved by the US Food and Drug Administration (FDA).[4] In addition, the test considered by some to be unsafe, as it uses a preparation derived from pus aspirated from suppurative lymph nodes of patients with CSD, and there is concern over the potential transmission of hepatitis viruses, HIV, and prions.

Computed Tomography

In patients with disseminated CSD and persistent high fever, abdominal pain, and severe systemic symptoms, abdominal CT scanning may be helpful. Multiple lesions of the liver and spleen are the major manifestations seen on such scans.

These lesions are usually round or oval, ranging from 3-30 mm, and hypodense on noncontrast CT scans.[53] Injection of contrast material may yield hypodense, isodense, or marginally enhanced lesions when compared with normal parenchyma. Hepatosplenic lesions have been observed to spontaneously resolve or calcify over weeks to months.

Histologic Findings

The primary inoculation lesion site consists of variously shaped (round, triangular, stellate) areas of necrosis or necrobiosis surrounded by an inner zone of palisading epithelioid histiocytes with a few multinucleated giant cells and an outer zone of lymphocytes. Organisms (visualized with the Warthin-Starry stain or the Brown-Hopp modification of the Gram stain) appear in the necrotic areas singly, in chains, or in clusters.

Huang et al reported that with Warthin-Starry stain, the organisms were located outside the cells and were mainly in the necrotic debris, especially near the nodal capsule, while BhmAB immunostain showed the same localization but organisms were seen as dotlike granular, as well as a few linear, positive signals.[52]

Histopathologic findings of the lymph nodes depend on the stage of infection. Lymphoid hyperplasia with arteriolar proliferation, reticulum cell hyperplasia, and widening of arteriolar walls are seen early in the disease. Progression of the disease is manifested by granulomas. The centers of these granulomas are acellular and necrotic with surrounding histiocytes and lymphocytes. Microabscesses may develop as the granulomas and areas of necrosis coalesce.

Lymphogranuloma inguinale, atypical mycobacteriosis, yersiniosis, tularemia, brucellosis, and chronic granulomatous disease of childhood may have histologic features similar to those of catscratch disease and should be considered in the differential diagnosis.

Histopathological examination of lymph nodes requires an invasive procedure; standard pathologic stains and Warthin Starry silver stain are nonspecific, and the staining procedure with the latter stain is technically difficult.[12] The specificity of staining is improved with the use of immunohistochemical assay.[54]

Warthin-Starry staining of involved lymph nodes may reveal chains, clumps, or clusters of pleomorphic B henselae bacilli. Organisms line the vascular sinuses. When necrosis is present, organisms may be seen within histiocytes as well as extracellularly in the necrotic areas and in the lumina of thrombosed blood vessels. Organisms are fewer in number in necrotic areas extensively infiltrated with neutrophils.

In many lymph nodes negative by culture, Rolain et al observed bacteria by direct immunofluorescence, which suggests that bacteria in lymph nodes are not viable.[24]

In patients with hepatic involvement, hepatic parenchyma may be replaced by zones of organizing granulation tissue containing focal areas of granulomatous inflammation with stellate areas of central necrosis. The necrotic areas are infiltrated with neutrophils and are surrounded by palisading fibroblasts.

 

Treatment

Approach Considerations

Controlled studies on treatment of catscratch disease (CSD) are lacking. Thus, treatment recommendations are based on case reports, reviews, a single controlled trial, and anecdotal data. Practice guidelines for the diagnosis and management of skin and soft-tissue infections, including CSD, have been established.[55]

For most patients with mild or moderate CSD, only conservative symptomatic treatment is recommended because the disease is self-limited. Administer antipyretics and analgesics as needed. Local heat may be applied to the involved lymph nodes.

Occasionally, lymph node aspiration is indicated for pain relief in patients with tender, fluctuant nodes. Use of antibiotics is controversial and not indicated for typical CSD in immunocompetent patients.

The role of corticosteroids in atypical CSD is somewhat controversial. Patients with neuroretinitis, encephalopathy with or without hemiplegia, and acute solid organ transplant rejection[56] have all been treated successfully with a combination of appropriate antibiotics and steroid therapy.

Antibiotic Treatment

Antibiotics are not indicated in most cases of CSD, but they may be considered for severe or systemic disease. Reduction of lymph node size has been demonstrated with a 5-day course of azithromycin[57] and may be considered in patients with severe, painful lymphadenopathy; however, no reduction in the duration of symptoms has been shown. Immunocompromised patients should be treated with antibiotics because they are particularly susceptible to systemic disease and bacteremia

Margileth et al reported the results of therapy for catscratch antigen–proven CSD with 18 different antimicrobials in 268 adult and pediatric patients.[58] They concluded that the following 4 antibiotics were the most effective for patients with severe CSD:

  • Rifampin - Efficacy of 87%

  • Ciprofloxacin - Efficacy of 84%

  • Gentamicin intramuscularly - Efficacy of 73%

  • Trimethoprim/sulfamethoxazole (TMP-SMZ) - Efficacy of 58%

These agents were considered moderately to highly effective, producing reduction or resolution of lymphadenopathy, a declining erythrocyte sedimentation rate, and decreased inflammatory and constitutional symptoms within 3-10 days. Severe disease was defined as persistent high fever (>103.1°F [>39.5˚C]) with severe systemic signs (eg, malaise, fatigue, blindness, headache) and lymphadenitis.

A prospective, randomized, double-blind, placebo-controlled study by Bass et al showed that azithromycin administered for 5 days decreased lymph node volume as measured by ultrasonography within the first month of treatment. No other differences in clinical outcome were noted.[57] Musso et al[59] found that aminoglycosides were bactericidal and Ives et al[60] showed that clarithromycin and azithromycin were efficacious in CSD. (See Table 3, below.)

Table 3. Response to Medications (Open Table in a new window)

Ciprofloxacin

500 PO bid

Case Report

5 adults

"Dramatic improvement" in a few days; defined as resolution of symptoms (ie, malaise and pain)

Holley[61]

Gentamicin

5 mg/kg/d IV/IM

Case Report

3 febrile children; 2 with hepatitis, 1 with painful regional lymphadenopathy

Resolution of fever and systemic symptoms in 1-2 days

Bogue et al[62]

TMP-SMZ

6-8 mg TMP/kg/d PO

Uncontrolled retrospective study

60 patients with prolonged fever and systemic symptoms

58% effective, 7-day course (see above)

Margileth[41]

Rifampin 10-20 mg/kg/d PO/IV

Uncontrolled retrospective study

60 patients with prolonged fever and systemic symptoms

87% effective, 7- to 14-day course (see above)

Margileth[58]

Azithromycin

500 mg PO qd for 1 day, then 250 mg PO qd for 4 days

Prospective placebo-controlled, double-blind study

29 patients

80% of lymph node volume (as measured by ultrasonography) resolved in 30 days in 7 of 15 patients on azithromycin vs 1 of 15 control patients

Bass et al[57]

Although data are lacking, patients with catscratch disease who are treated should receive treatment for 10-14 days. Immunocompromised patients may require much longer courses of therapy. No specific dose recommendations are available for treating CSD.

Somewhat paradoxically, patients with AIDS and bacillary angiomatosis-peliosis frequently respond to a variety of commonly used antibiotics. Response to erythromycin, isoniazid, rifampin, doxycycline, and ethambutol is reported by Koehler et al.[63, 64] If an immunocompromised patient has treatment relapse, then prolonged treatment (4-6 mo) is recommended, although this is based on anecdotal data.

Bartonella henselae is generally resistant to penicillin, amoxicillin, and nafcillin.

Patients with neurologic bacillary angiomatosis or ocular manifestations have improved with antibiotic therapy and supportive care or with supportive care alone. In patients with thoracic and/or pulmonary disease, especially in association with prolonged fever and systemic symptoms, a trial of oral TMP-SMZ, ciprofloxacin, or azithromycin 2-3 times daily for 7-21 days is recommended. In the rare case of a severely ill patient, intramuscular gentamicin 5 mg/kg/d may be effective within 72 hours; continue treatment for 6-8 weeks.

Normal doses of rifampin are 10-20 mg/kg/d orally every 12-24 hours, not to exceed 600 mg/d. Rifampin can cause hepatitis, particularly with underlying liver damage. Gastrointestinal, hematologic, and neurologic adverse effects are reported.

Importantly, because of the potential risk of arthropathy, caution should be used if considering the use of fluoroquinolones in patients younger than 18 years. Ciprofloxacin is not approved for administration in children. Additional adverse effects include gastrointestinal symptoms, dizziness, rash, seizures, headache, confusion, and tremors.

TMP-SMZ doses can include 8-12 mg/kg/d orally of TMP and 40-60 mg/kg/d orally of SMX every 12 hours. TMP-SMZ can cause rashes and, occasionally, Stevens-Johnson syndrome. Anemia and neutropenia may occur, and a mild decrease in platelet count is common.

The dose of intravenous gentamicin is 3-7.5 mg/kg/d orally every 8 hours. Serious toxic effects from these drugs are not common. Gentamicin may cause nephrotoxicity and ototoxicity. Aminoglycoside therapy is recommended for endocarditis.

Treatment of Lymph Node Suppuration

If suppuration occurs, lymph node aspiration may be required. Aspiration of suppurating nodes is both a diagnostic and therapeutic procedure. Repeated aspirations may be performed if pus reaccumulates and pain recurs.

Treat recurrence of suppuration by incision and drainage. Although incision and drainage has been discouraged because it leaves a scar and may result in a draining fistula, the risk of fistulous sinus tract formation is small. This has been reported only in cases of atypical mycobacterial lymphadenopathy mistaken for CSD.

Surgical excision of an enlarged node is indicated when the diagnosis is in question or when repeated aspirations fail to relieve the patient's pain. Excision of a persistent ocular granuloma may be required.

Follow-up

Immunocompetent patients and immunocompromised patients without evidence of systemic disease may be followed on an outpatient basis. Depending on severity, immunocompromised patients or patients with atypical manifestations of CSD may require hospitalization. If admission is required, frequent monitoring of the adenitis is indicated to evaluate for suppurative complications.

Outpatients should be instructed to return for a follow-up evaluation to ensure resolution of lymphadenopathy in 2-4 months. Patients should return to care sooner if their condition worsens or the lymph node starts to suppurate. Closely follow up patients for 6 months or until the lymphadenopathy resolves.

Neurologic complications can occur up to 6 weeks after inoculation. Instruct parents to seek medical attention if they notice any abnormal behavior in their children.

If the lymphadenitis does not resolve or if it progressively enlarges, surgical biopsy may be indicated to rule out neoplastic causes and to definitively diagnose catscratch disease.

Deterrence/Prevention

Pet quarantine, disposal, or euthanasia is unnecessary. The ability of the animal to transmit the organism is transient.

Although doxycycline treatment of cats is associated with decreased B henselae bacteremia, this treatment has not been shown to reduce the risk of cat-to-human transmission.

The natural history of feline infection and infectivity remains unknown. Feline B henselae bacteremia has been reported to last from weeks to months, with 100-fold fluctuations in bacteremic levels and intermittent negative cultures.

Given the established link between flea infection and B henselae transmission, common sense measures seem prudent (eg, avoiding stray cats, keeping pets free of fleas).

Children should be taught how to handle pets gently. Any scratch or bite, especially from a kitten, should be brought to the attention of parents and carefully followed up.

Consultations

Emergent consultation is not usually required for those with catscratch disease. Consider emergent or outpatient consultation in cases of diagnostic uncertainty or with specific organ system involvement as indicated.

Consultation with an infectious disease specialist should be sought in cases of atypical catscratch disease or in cases of catscratch disease in immunocompromised patients. Consultation with a neurologist is indicated for patients with CNS involvement, and evaluation with an ophthalmologist may be needed in patients with any visual changes.

 

Medication

Medication Summary

In general, treatment beyond analgesia and recommendation for warm compresses is unnecessary for patients with catscratch disease (CSD) because the condition spontaneously resolves without sequelae in most cases.

Currently, only limited and/or anecdotal evidence supports the use of antibiotics in the treatment of typical CSD in immunocompetent hosts. Bartonella henselae is susceptible to many antibiotics in vitro. However, the susceptibility patterns do not predict efficacy in vivo. Bartonella is an intracellular bacterium and responds poorly to penicillin derivatives in vivo despite susceptibility in vitro.

A single treatment for all Bartonella -related diseases has not been identified, so treatment must be tailored to specific situations. Immunocompromised patients tend to develop more-severe Bartonella infections and may require prolonged antibiotic treatment.

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

Antibiotics

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. These agents reduce the duration of lymphadenopathy and decrease constitutional symptoms. B henselae, a gram-negative bacillus, is sensitive to various antibiotics in vitro. Few clinical studies are available, but not all of the antibiotics to which the organism is sensitive in vitro are effective in vivo.

Azithromycin (Zithromax, Zmax)

This agent inhibits RNA-dependent protein synthesis at the chain elongation step. It Acts by binding to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis is not affected.

Azithromycin concentrates in phagocytes and fibroblasts, as demonstrated by in vitro incubation techniques. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.

This agent treats mild-to-moderate microbial infections. Plasma concentrations are very low but tissue concentrations are much higher, giving it value in treating intracellular organisms. It has a long tissue half-life.

Doxycycline (Doryx, Doxy, Periostat, Vibramycin)

Doxycycline 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.

Ciprofloxacin (Cipro, Proquin XR)

Ciprofloxacin is a fluoroquinolone with activity against pseudomonads, streptococci, methicillin-sensitive Staphylococcus aureus (MSSA), S epidermidis, and most gram-negative organisms. It has no activity against anaerobes. This agent inhibits bacterial DNA gyrase and consequently growth; it inhibits relaxation of supercoiled DNA and promotes breakage of double-stranded DNA. Continue treatment for at least 2 d after signs and symptoms have disappeared (7-14 d typically).

Rifampin (Rifadin)

Rifampin inhibits bacterial RNA synthesis by binding to the beta subunit of DNA-dependent RNA polymerase, blocking RNA transcription.

Erythromycin (E.E.S., Erythrocin, Ery-Tab, EryPed)

Erythromycin inhibits RNA-dependent protein synthesis at the chain elongation step; it binds to the 50S ribosomal subunit, resulting in blockage of transpeptidation.

Gentamicin

Gentamicin is an aminoglycoside antibiotic for gram-negative coverage. This agent binds bacterial 30S and 50S ribosomal subunits. It is used in combination with both an agent against gram-positive organisms and an agent that covers anaerobes.

Gentamicin is not the drug of choice for CSD. Consider using it if penicillins or other less toxic drugs are contraindicated, when clinically indicated, and in mixed infections caused by susceptible staphylococci and gram-negative organisms.

Dosing regimens are numerous; adjust dose based on creatinine clearance (CrCl) and changes in volume of distribution. Gentamicin may be given IV or IM. Follow each regimen by at least a trough level drawn on the third or fourth dose (0.5 h before dosing); a peak level may be drawn 0.5 h after 30-min infusion.

Trimethoprim and sulfamethoxazole (Bactrim DS, SeptraDS)

This combination agent inhibits bacterial growth by inhibiting dihydrofolate reductase, depleting folic acid. Its antibacterial activity includes common urinary tract pathogens, except Pseudomonas aeruginosa.

Clarithromycin (Biaxin)

Clarithromycin is a semisynthetic macrolide antibiotic that reversibly binds to P site of 50S ribosomal subunit of susceptible organisms. It may inhibit RNA-dependent protein synthesis by stimulating dissociation of peptidyl t-RNA from ribosomes, causing bacterial growth inhibition.

 

Questions & Answers

Overview

What is cat scratch disease (CSD)?

What are the systemic symptoms of cat scratch disease (CSD)?

What is the symptoms of cat scratch disease (CSD) in immunocompromised patients?

How is cat scratch disease (CSD) differentiated from lymphadenopathy?

When was cat scratch disease (CSD) first described?

Who discovered cat scratch disease (CSD)?

What is Foshay’s contribution to the understanding of the etiology of cat scratch disease (CSD)?

What is the history of cat scratch disease (CSD) in the 1950s?

When was the spectrum of catscratch disease (CSD) first detailed?

What is the importance of molecular taxonomy in the understanding of the pathogenesis of cat scratch disease (CSD)?

What is the etiologic agent for cat scratch disease (CSD)?

What is the first successful isolation and culture of the cat scratch disease (CSD) organism?

What is the role of Rochalimaea henselae in the etiology of cat scratch disease (CSD)?

How is bacillary angiomatosis manifested in cat scratch disease (CSD)?

What is the most common cause of cat scratch disease (CSD)?

What is the pathophysiology of cat scratch disease (CSD)?

What is the role of outer membrane proteins (OMPs) of B henselae in the etiology of cat scratch disease (CSD)?

What is the role of feline infection with Bartonella (B) henselae in the pathogenesis of cat scratch disease (CSD)?

What is the role of fleas in the pathogenesis of cat scratch disease (CSD)?

What is the role of familial factors in the transmission of cat scratch disease (CSD)?

What is the prevalence of Bartonella (B) henselae among family members of patients with cat scratch disease (CSD)?

Which organ systems are affected by cat scratch disease (CSD)?

How are the lymph nodes affected by cat scratch disease (CSD)?

What is the most common neurologic manifestation of cat scratch disease (CSD)?

How is neuroretinitis manifested in cat scratch disease (CSD)?

What are the pulmonary manifestations of cat scratch disease (CSD)?

How do vertebral osteomyelitis and splenic abscess manifest in patients with cat scratch disease (CSD)?

What is the usual cause of cat scratch disease (CSD)?

What are the natural reservoir and vectors for transmission of cat scratch disease (CSD)?

How does the transmission of Bartonella (B) henselae from cats to humans occur?

Why are kittens the main source of cat scratch disease (CSD)?

Other than scratches, how is cat scratch disease (CSD) transmitted in humans?

What is known about familial outbreaks of cat scratch disease (CSD)?

What are rare causes of cat scratch disease (CSD)?

What is the incidence of cat scratch disease (CSD) in the US?

In what regions of the US is the incidence of cat scratch disease (CSD) highest?

During what time of the year do most cat scratch disease (CSD) cases occur in the US?

What is the hospitalization rate for cat scratch disease (CSD)-in the US?

What is the global incidence of cat scratch disease (CSD)?

During what time of the year do the majority of cat scratch disease (CSD) cases occur?

Which phenotypes of Bartonella (B) henselae are pathogenic for cat scratch disease (CSD) globally?

How does the incidence of cat scratch disease (CSD) vary by sex?

How does the prevalence of cat scratch disease (CSD) vary by age?

What is the prognosis of cat scratch disease (CSD)?

What is the durations of lymphadenitis in cat scratch disease (CSD) resolve?

What is the course of cat scratch disease (CSD) in immunocompromised patients?

What is the included in the patient education information for cat scratch disease (CSD)?

Presentation

What is the most common presentation of catscratch disease (CSD) in patients seeking medical care?

Which history is characteristic of cat scratch disease (CSD)?

What is the initial symptom of cat scratch disease (CSD)?

How does lymphadenopathy develop in patients with cat scratch disease (CSD)?

What are the characteristics of lymphadenopathy in cat scratch disease (CSD)?

What are systemic symptoms of cat scratch disease (CSD)?

What are the central nervous system (CNS) symptoms of cat scratch disease (CSD)?

How was the diagnosis of cat scratch disease (CSD) confirmed?

What are unusual presentations of cat scratch disease (CSD)?

What differences have been noted between the presentation of typical cat scratch disease (CSD) and that of severe disease?

How are skin eruptions characterized in severe cat scratch disease (CSD)?

Which finding is evidence of recurrent cat scratch disease (CSD)?

Which physical findings are characteristic of cat scratch disease (CSD)?

Where are inoculation papules of cat scratch disease (CSD) typically located?

How is rash characterized in cat scratch disease (CSD)?

How are infected nodes characterized in cat scratch disease (CSD)?

What are the most common locations for lymphadenopathy in cat scratch disease (CSD)?

How frequently does suppuration occur in cat scratch disease (CSD)?

How is conjunctival cat scratch disease (CSD) manifested?

How frequently is fever manifested in cat scratch disease (CSD)?

What is a presentation of cat scratch disease (CSD) with fever?

What are symptoms of cat scratch disease (CSD)?

What is an unusual otolaryngologic presentation of cat scratch disease (CSD)?

What are the less common symptoms of cat scratch disease (CSD)?

What are some atypical manifestations of cat scratch disease (CSD)?

What is Parinaud oculoglandular syndrome (POS) in cat scratch disease (CSD)?

How does Parinaud oculoglandular syndrome (POS) manifest in cat scratch disease (CSD)?

Which physical findings are characteristic of Parinaud oculoglandular syndrome (POS) in cat scratch disease (CSD)?

Which central nervous system (CNS) findings suggest cat scratch disease (CSD)?

How is encephalopathy manifested in cat scratch disease (CSD)?

How is encephalitis manifested in cat scratch disease (CSD)?

How is cat scratch disease (CSD) with CNS involvement diagnosed?

What is the disease progression of cat scratch disease (CSD) encephalitis?

How does transverse myelitis present in cat scratch disease (CSD)?

How are the cranial or peripheral nerves involved in cat scratch disease (CSD)?

How is neuroretinitis manifested in cat scratch disease (CSD)?

How is the eye affected in cat scratch disease (CSD)?

What is the recovery time from central nervous system (CNS) manifestations of cat scratch disease (CSD)?

What is hepatosplenic cat scratch disease (CSD)?

What are the physical findings in hepatosplenic cat scratch disease (CSD)?

How is hepatosplenic cat scratch disease (CSD) diagnosed?

What are the treatment options for hepatosplenic cat scratch disease (CSD)?

How is endocarditis manifested in cat scratch disease (CSD)?

What are the treatment options for endocarditis in cat scratch disease (CSD)?

Where does osteomyelitis manifest in patients with cat scratch disease (CSD)?

What are the roles of imaging studies in the diagnosis of osteomyelitis in cat scratch disease (CSD)?

How is osteomyelitis presented in cat scratch disease (CSD)?

What are the uncommon dermatologic manifestations of cat scratch disease (CSD)?

How does cat scratch disease (CSD) manifest in immunocompromised patients?

How does bacillary angiomatosis manifest in immunocompromised patients with catscratch disease (CSD)?

How does bacillary peliosis manifest in immunocompromised patients with catscratch disease (CSD)?

DDX

How is cat scratch disease (CSD) differentiated from other causes of lymphadenopathy?

What should be included in the differential diagnoses of cat scratch disease (CSD) in immunocompromised patients?

What are the differential diagnoses for Cat Scratch Disease (Cat Scratch Fever)?

Workup

What is the diagnostic approach for cat scratch disease (CSD)?

What is the diagnostic approach for cat scratch disease (CSD) in immunocompromised patients?

What is the role of serologic testing in the diagnosis of cat scratch disease (CSD)?

What is the efficacy of indirect fluorescence assay (IFA) testing for the diagnosis of cat scratch disease (CSD)?

What is the efficacy of Enzyme-linked immunoassay (ELISA) testing for the diagnosis of catscratch disease (CSD)?

What is the role of immunoglobulins testing in the diagnosis of cat scratch disease (CSD)?

What is the prevalence of seropositivity in cats living with a human with cat scratch disease (CSD)?

When is lymph node biopsy indicated in the diagnosis of cat scratch disease (CSD)?

How are Bartonella (B) species differentiated in cat scratch disease (CSD)?

What is the sensitivity of polymerase chain reaction (PCR) in the diagnosis of cat scratch disease (CSD)?

What are the histopathological findings characteristic of cat scratch disease (CSD)?

What are the histopathological features for cat scratch disease (CSD)?

What is the limitations of Bartonella (B) culturing in the diagnosis of cat scratch disease (CSD)?

What is the role of biopsy in the diagnosis of cat scratch disease (CSD)?

What is the role of skin testing in the diagnosis of cat scratch disease (CSD)?

What is the role of CT scanning in the diagnosis of cat scratch disease (CSD)?

What are histologic characteristics of primary inoculation lesions in cat scratch disease (CSD)?

Which findings with Warthin-Starry stain are characteristics of cat scratch disease (CSD)?

Which histopathologic findings are characteristic of lymph nodes in cat scratch disease (CSD)?

Which diseases have histologic features similar to those of cat scratch disease (CSD)?

How is histopathologic exam of lymph nodes performed in cat scratch disease (CSD)?

What is the role of Warthin-Starry staining in the diagnosis of cat scratch disease (CSD)?

Which findings suggest the bacteria in the lymph nodes is not viable in cat scratch disease (CSD)?

What are the histologic findings characteristic of cat scratch disease (CSD) with hepatic involvement?

Treatment

What is the basis for treatment recommendation for cat scratch disease (CSD)?

What are the treatment options for mild or moderate cat scratch disease (CSD)?

When is lymph node aspiration indicated in the treatment of cat scratch disease (CSD)?

What is the role of corticosteroids in the treatment of cat scratch disease (CSD)?

What is the role of antibiotics in the treatment of cat scratch disease (CSD)?

Which antibiotics are effective for the treatment of severe cat scratch disease (CSD)?

What is the role of azithromycin in the treatment of cat scratch disease (CSD)?

What is the duration of antibiotic treatment for cat scratch disease (CSD)?

Which antibiotics are used in the treatment of acquired immunodeficiency syndrome (AIDS) and bacillary angiomatosis-peliosis due to cat scratch disease (CSD)?

Which antibiotics are less effective in the treatment of cat scratch disease (CSD)?

Which complications of cat scratch disease (CSD) are treated with antibiotics?

What is the regimen for rifampin in the treatment of cat scratch disease (CSD)?

What are possible adverse effects of fluoroquinolones for the treatment of cat scratch disease (CSD)?

What are the possible adverse effects of trimethoprim/sulfamethoxazole (TMP-SMZ) for the treatment of cat scratch disease (CSD)?

What are possible adverse effects of IV gentamicin in the treatment of cat scratch disease (CSD)?

How is suppuration treated in catscratch disease (CSD)?

How is recurrence of suppuration treated in cat scratch disease (CSD)?

What is the role of surgical excision in the treatment of cat scratch disease (CSD)?

When is inpatient treatment indicated for cat scratch disease (CSD)?

What monitoring is needed following treatment of cat scratch disease (CSD)?

How are neurologic complications of cat scratch disease (CSD) managed?

When is surgical biopsy indicated in the management of cat scratch disease (CSD)?

When is pet quarantine required in the deterrence of cat scratch disease (CSD)?

What is the role of doxycycline in the prevention of cat scratch disease (CSD)?

What is the natural history of feline infection and infectivity with cat scratch disease (CSD)?

How is cat scratch disease (CSD) prevented?

What education should be given to children for prevention of cat scratch disease (CSD)?

When is emergent consultation needed in the management of cat scratch disease (CSD)?

Which specialist consultation are helpful in the management of cat scratch disease (CSD)?

Medications

Which medications are used in the primary treatment of cat scratch disease (CSD)?

What is the efficacy for antibiotics in the treatment of cat scratch disease (CSD)?

How is cat scratch disease (CSD) treated in immunocompromised patients?

What are possible adverse effects of antibiotic therapy for cat scratch disease (CSD)?

Which medications in the drug class Antibiotics are used in the treatment of Cat Scratch Disease (Cat Scratch Fever)?