Excerpt from Catscratch Disease

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Background

Catscratch disease (CSD), also known as catscratch fever or subacute regional lymphadenitis, is caused by infection with the gram-negative bacillus Bartonella henselae. Typically a benign and self-limited disease in patients who are immunocompetent, only a small percentage of patients have complications involving the skin, lymph nodes, eyes, liver, spleen, or nervous system. Infection of immunocompromised patients with the same organism leads to a very different disease, bacillary angiomatosis-peliosis, which is characterized by angioproliferative lesions resembling those of Kaposi sarcoma in the skin, liver, spleen, bone, and other organs.

Henri Parinaud¹ sometimes is given credit for the first description of CSD in 1889. However, his oculoglandular syndrome of conjunctivitis with an enlarged preauricular lymph node ultimately was shown to be 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.

The history of CSD has been reviewed comprehensively by Carithers² in 1970 and by Margileth³ in 1987 and is summarized here.

Debre and a colleague, 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 results⁴ were presented and published in 1950. 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 Keefer⁵ published the first report of CSD in American literature, in which they described a broader spectrum of CSD manifestations. In the late 1950s, William Warwick of the University of Minnesota collaborated with Robert Good, MD, 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. The first thorough review of the world's literature, published in 1967, included 567 references and detailed the manifold clinical presentations. The landmark publication⁶ of a series of 1200 cases evaluated by one observer put the varied clinical presentations into perspective and provided the first realistic analysis of the spectrum of disease.

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.⁷ In 1984, Margileth et al,⁸ using the same staining technique, demonstrated identical organisms in biopsy specimens taken from CSD inoculation papules. The first successful isolation and culture of the CSD organism was performed by English et al⁹ in 1988. 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 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.¹⁰

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

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 al¹¹ 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. Carithers⁶ found similar results in a series of 1200 patients; 18.5% of asymptomatic family members had positive CSD antigen skin test results.

Frequency

United States

CSD is not a reportable infection. Seroprevalence rates vary greatly throughout the world, ranging from 0.6-37%. Approximately 22,000 cases occur annually in the United States. The prevalence is estimated to be 9.3 cases per 100,000 population. 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. Incidence peaks in the fall and winter months. These trends parallel the feline flea population density. The number of pediatric hospitalizations in the United States for CSD complications was estimated at 437 cases in 2000 children (0.60 in 100,000 children younger than 18 y and 0.86 in 100,000 children younger than 5 y).

Mortality/Morbidity

CSD generally is a self-limited infection, manifesting as a subacute regional lymphadenitis persisting for 3 weeks or more. Very few deaths (2 reported^{12, 13}) from CSD have occurred in immunocompetent patients. However, 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.

Race

CSD has no documented racial predisposition.

Sex

In some case series, a slightly higher incidence of CSD appears to occur in male patients, 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.

Age

CSD affects persons in all age groups, but most patients are 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). A bias may exist in the literature because pediatricians have collected many of the large case series. Adults are more likely to manifest atypical features of CSD.

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