++
Cat scratch disease (CSD) is a ubiquitous, self-limited infection
characterized by prolonged regional lymphadenitis and often an inoculation
site papule, usually after a cat’s (frequently a kitten’s) scratch
or bite, and caused primarily by Bartonella henselae.
In 10% to 20% of cases, the lymph node will suppurate.1,2 In
a minority of cases (approximately 10%), a wide range of
extranodal manifestations collectively known as atypical CSD may
occur, including fever of unknown origin, as well as visceral, neurologic,
and ocular involvement. In immune competent individuals, prognosis
is generally good, but infection may be life-threatening and its
manifestations different in the immune compromised.
+++
Epidemiology
and Pathophysiology
++
CSD occurs worldwide and is prevalent in warm and humid climates.
In temperate zones, CSD occurs primarily during fall and winter,
sometimes also during the summer, while in the tropics, it occurs
throughout the year.1-3 CSD was, in the past, considered
to be mainly a disease of children and adolescents, about 55% males,
with approximately 90% of patients younger than 18 to 21
years old.1 Newer studies, however, have reported
that 45% and 43% of CSD patients are more than 18
and 20 years of age, respectively.4,5 CSD almost
never occurs in children under 2 years of age and is increasingly
recognized in all age groups, including the elderly.6 Intrafamilial clustering
of CSD occurs rarely,7 though anti-B henselae seropositivity
is more frequent in families with a case of CSD than in the general population,
indicative of asymptomatic infection.5 Immune deficient
people, especially those with HIV, may become severely ill with a
unique spectrum of disease.2,8 In 1993, the annual
incidence of CSD in the United States was estimated at 9 to 10/100,000
with about 10% hospitalization, and most patients were younger
than 21 years old.4 However, indirect transmission
of B henselae by red cell transfusion may be possible.19 In
2000, the US annual hospitalization rate for CSD was estimated at 0.6/100,000
and 0.86/100,000 for children under 18 and under 5 years
old, respectively; not surprisingly 24% of admissions were
for atypical disease, 12% central nervous system (CNS)
and 7% visceral.9 Cats, especially kittens
under 1 year of age, are the major reservoir and tend to have prolonged, asymptomatic
intraerythrocytic bacteremia. They infect humans by scratch, bite,
or mucous membrane (conjunctival, respiratory) inoculation.2,5,10-14 The
cat flea, Ctenocephalides felis, is associated
with increased cat infectivity and with cat-to-cat transmission
of B henselae although it probably does not play
a major role in cat-to-human B henselae transmission.5,11,15 The
observation that in temperate zones CSD incidence peaks in fall
and winter while flea infestation of cats primarily occurs during
spring and summer argues against the role of the cat flea in human
CSD pathogenesis. Felids, dogs, monkeys, and other animals may harbor B henselae,
and some have been anecdotally associated with CSD. Inanimate objects
(eg, thorns, splinters, fencing) probably also cause CSD, though
overall, approximately 90% of CSD is cat associated.16 Certain
ticks can harbor B henselae, but their role in
human disease is as yet undefined.17,18 Direct
human-to-human spread has not been reported; however, indirect transmission
of B henselae by red cell transfusion may be possible.19
++
Bartonellae are fastidious, slow-growing, pleomorphic gram-negative Proteo bacteria,
related to Brucella. All Bartonella spp
can be cultured on cell-free media (eg, rabbit-heart infusion or
chocolate agar plates). Results are optimized if media are fresh. Culture
of B henselae may require several weeks of incubation
before colonies can be detected. Routine bacterial cultures in
the clinical microbiology laboratory are not likely to detect Bartonella growth. Although B
henselae can be frequently isolated from infected cats,
sensitivity of blood or lymph node cultures is extremely low in
immunocompetent patients with cat scratch disease (CSD). Therefore,
cultures are not recommended for the routine diagnosis of most CSD
cases.20B bacilliformis, B quintana,
and B henselae are the most important human pathogens,
but other Bartonellae (eg, B elizabethiae, B kohlerae, and B
clarridgeiae) also cause human disease.20 CSD
was clinically recognized in the early 20th century and was first
described in 1950 by Debré.21 In 1983,
organisms were visualized by silver staining of CSD lymph nodes.22 In
1988, Afipia felis, a rare cause
of CSD, was isolated,23 and finally, in the 1990s, B
henselae was proven the major cause of CSD—epidemiologically,
serologically, by culture, and by molecular methods.20 Recently, B.
clarridgeiae was reported to be another minor cause of
CSD.24 The pathogenesis of CSD is poorly understood,
and the reasons some patients develop typical CSD with localized
infection and regional necrotizing granulomatous adenitis while
others develop serious atypical disease, presumably due to blood-borne
dissemination with visceral or other end-organ involvement, is not
clear. Bacterial and host factors play a role. B henselae strains
particularly associated with human disease (eg, ST1 genotype) or
with only cat infection (eg, ST7 genotype) were identified.25 The type
and severity of the host immune response to infection also modify
the clinical picture.26,27 Immunocompromised individuals,
especially those with cell-mediated immune deficiency, either congenital
or acquired (especially HIV-AIDS), are at risk of developing severe or
atypical disease.2,20,28B henselae can
infect and persist in CD34+ differentiating hematopoietic
progenitor cells29; like other Bartonellae, it
interacts with endothelial cells and is capable of inducing angiogenesis.30B
henselae can induce a Th1 inflammatory response, and IFNg
and nitric oxide play important roles.30,31 Dendritic
cells and humoral immunity also play a role in the host response to B
henselae.32
++
Typical
cat scratch disease (CSD) is probably the most common cause of prolonged
subacute regional lymphadenitis in children.2,33 Cutaneous
inoculation of B henselae is 90% cat,
especially kitten-associated, 50% to 75% of which
is via scratch or bite.1,2,16,33 A few days to
a few weeks later, often unrecognized by the patient, a 2- to 5-mm
erythematous, nonpainful papule appears at the inoculation site
in up to two thirds of patients (Figure 257-1)
and persists for a few weeks.1,2,16,33B henselae can
be found in these lesions (Fig. 257-1). When
inoculation is presumably respiratory and involves mucous membranes
(especially about the head and neck), inoculation lesions are absent.
The hallmark of typical CSD is chronic regional lymphadenitis in
a node or nodes draining the site of inoculation. Most frequently,
CSD involves a solitary lymph node or a group of nodes at a single
site, while only rarely will CSD manifest as generalized adenopathy.1,2 Usually
tender initially, often remaining tender, these nodes appear from
1 week to 1 to 2 months after inoculation. Size may vary from 1
to 2 cm to 5 to 10 cm, and erythema of the overlying skin may occur (eFigs. 257.1 and 257.2).
Suppuration occurs in 10% to 20%1,2,16,33 and
drainage of pus may persist for weeks. CSD is primarily an infection
of the nodes draining the upper extremity, head, neck, and groin,
but any lymph node location is possible.1,2,16,33 Epitrochlear
lymphadenopathy with or without axillary adenopathy is typical though
not pathognomonic of CSD (eFigure 257.3).
Between 30% and 50% of patients will have an elevated
temperature that can be accompanied by malaise, anorexia, night
sweats, headache and other nonspecific complaints, all of which
are more prominent with increasing age.1,2,16 Resolution
is usually over weeks to a few months, though rarely, recovery may
be prolonged, over a year or more.
++
++
++
++
++
The causes of regional adenopathy/adenitis with or without
an inoculation lesion are numerous.34,35 The prolonged course
of CSD lymphadenopathy, often without the stigmata of pyogenic lymphadenitis (eg,
local erythema, warmth, and leukocytosis), particularly when accompanied
by fever, night sweats, or weight loss, may mimic malignancy, especially
lymphoma, and is often a cause of serious concern for both the patient, the
parents, and the treating physician. Maintaining a high index of
suspicion and taking a detailed history, particularly that of cat
contact, are important in making the correct diagnosis and thus
avoiding diagnostic procedures that are often unnecessary (eg, computerized tomography [CT] scan,
biopsies). Infection is most commonly
the cause of regional adenopathy/adenitis: bacterial—staphylococcal,
streptococcal, Erysipelothrix rhusiopathiae, possibly
tularemia, brucellosis, plague, syphilis, Lyme disease, LGV, anthrax;
higher bacteria—actinomycosis, nocardia; mycobacterial—tuberculosis
and especially atypical mycobacteria (usually in the very young,
< 3 years old); fungal—blastomycosis, histoplasmosis,
coccidiomycosis, sporotrichosis; viral—EBV, CMV, HIV; parasitic—toxoplasmosis.
The possibility of malignancy, especially lymphoma, or of a benign
tumor must be entertained. Noninfectious, nonneoplastic causes include sarcoidosis,
Kawasaki disease, sinus histiocytosis with massive lymphadenopathy,
congenital neck anomalies, autoimmune lymphoproliferative syndrome,
histiocytic necrotizing lymphadenitis (Kikuchi disease), sometimes
possibly due to B henselae,36 idiopathic
facial aseptic granuloma, and drug-induced lymphadenopathy (eg,
due to phenytoin). Other than as suggested by one recent report,34 CSD
rarely coexists with another pathological entity.
++
The
term atypical CSD (cat scratch disease) is confusing
and should be replaced by “extranodal CSD” or “complicated
CSD.” In immune competent children, typical CSD (regional lymphadenopathy)
occurs in 85% to 90%, and atypical or complicated
CSD in the remainder.1,2,16,33 Occasionally, B
henselae disseminates to liver, spleen, eye, CNS, bone,
and other sites. Even these manifestations are usually self-limited,
and recovery without sequelae is usually the rule. The most common atypical
presentation of CSD (about 50% of all atypical CSD) is
Parinaud oculoglandular syndrome (eFig. 257.4),
where the patient has granulomatous conjunctivitis and preauricular lymphadenitis.2,37,38 In
fact, this is actually typical CSD with conjunctival inoculation
and regional adenitis. Dissemination to viscera usually involves
liver or spleen, often with prolonged fever, abdominal pain, weight
loss, and tender visceromegaly, sometimes abnormal hepatocellular
enzymes, elevated ESR or CRP, and frequently without an inoculation site
or regional adenopathy.2,39,40 Ultrasound and CT
suggest microabscesses, which histologically are necrotizing granulomata
of liver or spleen. CSD is a common cause of FUO in children, and
FUO due to CSD may occur in the context of visceral dissemination
or in its absence.2,41-48 Eye manifestations other
than conjunctivitis include neuroretinitis, papillitis, optic neuritis,
focal retinochoroiditis, where most commonly the patient complains
of acute, usually unilateral, visual deterioration, and occurs in
about 2% of CSD. Optic nerve edema with stellate macular
exudates (“macular star”) is seen funduscopically
and can persist for months. This is associated with sequelae in
some, though most recover.2,37,42,43 Neurologic
complications (2–4% of CSD) include encephalopathy
with or without focal or generalized seizures, transverse myelitis,
radiculitis, cerebellar ataxia, cranial nerve palsies especially
of the facial nerve, and compression neuropathy.2,44-47 These
presentations can occur with or without typical CSD symptoms or
signs. Encephalopathy, the most common neurologic complication,
usually begins abruptly 1 to 4 weeks after exposure to B
henselae. Lumbar puncture is either normal or with a mild,
predominantly mononuclear pleocytosis, or mildly elevated CSF protein.
Culture is negative, CT is normal, and electroencephalogram (EEG)
is characteristically encephalopathic. Most recover within weeks
to months, sequelae are rare, but CNS involvement can be fatal.48 CSD
should be considered in any previously healthy school-aged child
with new onset status epilepticus.49 Other atypical
manifestations of CSD consist of osteomyelitis/osteolytic
granulomatous lesions including those of vertebrae and pelvis,50,51 possibly
multifocal osteomyelitis52; numerous rashes including
erythema nodosum, erythema multiforme, and vasculitic53,54;
deep neck space infection; arthropathy and musculoskeletal complaints (mostly
in adults)55,56; hypercalcemia57;
pneumonitis, thrombocytopenic purpura, hemolytic anemia, glomerulonephritis.2,58B
henselae has also been associated with Henoch Schönlein
purpura as determined in 2 small studies where the seropositivity
rate for B henselae was found to be significantly
higher than controls.59,60 Two very important kinds
of B henselae infection not within the scope of
this chapter are bacterial endocarditis, rare in children,2,20,33,61 and
infection of immunocompromised patients including vascular proliferative cutaneous
and visceral lesions of bacillary angiomatosis and bacillary peliosis,
and persisting or relapsing bacteremia.2,20,33
++
+++
Diagnostic Evaluation
++
Historically, diagnosis was made when a patient presented with
a cat scratch or bite, a primary inoculation lesion, regional lymphadenitis
and a characteristic biopsy, sterile pus or a positive skin test
with cat scratch antigen. Clinical suspicion in the appropriate
epidemiological context is still extremely important, but given
the expanded spectrum of CSD, specific diagnostic tools are required,
especially when a classical history is absent. Routine laboratory
tests are usually not helpful: WBC, ESR, CRP may be normal or elevated,
hepatocellular enzymes may be abnormal with visceral involvement,
and imaging (ultrasound, CT, magnetic resonance imaging [MRI])
is also nonspecific (eFig. 257.5). Culture of B henselae from blood or tissue is slow,
cumbersome, requires special and impractical techniques, and in
the immune competent host, negative cultures are the rule rather
than the exception. Skin test (prepared from pus aspirated from
affected lymph nodes of CSD patients) was deemed useful, but because
it was never standardized and is potentially dangerous, its use
has been discontinued, especially with current, better diagnostic
tools available.2,5 Biopsy of the inoculation papule
or lymph node (or deep lesions) shows a characteristic but nondiagnostic
histological picture with epithelioid granuloma and Langhan giant
cells. Later, necrotizing stellate granulomata are seen, and in
some nodes, microabscesses enlarge and coalesce, leading to suppuration. The
inflammatory process often involves surrounding tissue (eg, the
skin). When present (primarily early in the course of infection), B henselae may
be visualized by silver staining, but a positive stain for bacteria
is not specific.20 Immunohistochemical assays can
improve specificity but are of limited availability in routine diagnostic
laboratories.20 The most practical way to diagnose
CSD is serologically. The IgG-based immunofluorescent antibody test
(IFAT), such as that performed at the Centers for Disease Control and
Prevention, has a sensitivity of 84% to 95% and
a specificity of 94% to 98%.20 Results
from studies performed in Europe are less satisfactory and inconsistent,
perhaps due to higher background seroprevalence.62,63 Cross-reactivity
with other organisms including Bartonellae (eg, B quintana) has
been reported.20 Enzyme immunoassay (EIA) tests
are also used, but variable sensitivity is also a problem.64 An
outer-membrane protein-based EIA has a sensitivity of 85% (when
IgG and/or IgM anti-B henselae antibodies
are positive) and a specificity of 98% and can be useful
in differentiating old from acute disease.65,66 Both
IFAT and EIA antibodies develop slowly; thus, seroconversion may
occur only after ⩾ 3 weeks of illness. Repeat serological testing
may be required to make the diagnosis. Polymerase chain reaction
(PCR) of lymph node or pus aspirate, primary skin lesions or of
other tissue is a highly sensitive and specific diagnostic tool.
Both broad-range and species-specific PCR assays have been developed.
It is particularly useful when serology is negative and definitive
diagnosis is urgent (eg, in those who are particularly ill, who
have atypical disease or complications, whose lesions are not resolving,
the immune compromised, or when other diagnoses such as malignancy
are being entertained).67,68 Fine-needle aspiration
of a lesion for PCR and cultures may suffice, although excisional biopsy
is indicated when malignancy needs to be ruled out. One difficulty
is in considering the diagnosis of CSD, particularly atypical CSD,
in the absence of cat exposure or lymphadenopathy.
++
++
Few
studies, mostly small, anecdotal, or retrospective, have addressed
the question of therapy for CSD. In addition, in vitro susceptibility
testing does not correlate with in vivo results of therapy.69 Possible
explanations include the fact that lymph node disease may be host-response
driven, that most antibiotics are not bactericidal for Bartonellae,
and that the intracellular location of the bacteria may be protective.
A large, retrospective study showed that treating with rifampin,
ciprofloxacin, gentamicin, and trimethoprim-sulfamethoxazole resulted
in a shorter duration of disease when compared to no therapy or
to therapy with other antimicrobials.70 However,
it is difficult to draw conclusions from this retrospective review, especially
because CSD is a self-limited disease, and cure without sequelae
is the rule even without treatment. Only one small, randomized,
prospective, double-blind, placebo-controlled study was performed
to assess the effects of treating CSD: azithromycin reduced lymph
node volume significantly during 30 days posttherapy. Thereafter,
there were no differences noted.71 Antimicrobial
therapy for CSD has been reviewed critically, and some specific
recommendations for therapy have been made.70,72 It
is logical to conclude, due to the minimal effects of antibiotic
therapy on typical CSD (a self-limited disease with a good prognosis),
that many if not most nonimmunocompromised patients need not be
treated. Treatment should be limited to patients with moderate to
severe illness who have not begun to improve spontaneously (eg,
those with severe systemic symptoms, those whose nodes are large
and significantly painful). Azithromycin (10 mg/kg on day
1, 5 mg/kg on days 2 through 5) seems to be a reasonable choice
if treatment for typical CSD is desired. Doxycycline, rifampin,
ciprofloxacin, gentamicin, and trimethoprim-sulfamethoxazole may
be considered as alternatives. However, despite antimicrobial treatment,
many CSD patients have a prolonged course or develop lymph node
suppuration or complications. Symptomatic therapy including analgesics (eg,
NSAIDS) and locally applied warm compresses can relieve pain. Aspiration
of fluctuant, suppurating nodes with a 16- to 18-gauge needle (with
5% lidocaine-prilocaine cream, with or without midazolam)
yields thick, beige, odorless, often blood-tinged pus and will relieve
the associated discomfort (eFig. 257.6).
This may need to be repeated up to 2 to 3 times. Incision and drainage
should be avoided in order to prevent sinus formation with chronic
drainage. For the treatment of complicated CSD, no strong evidence-based recommendations
can be made, though various protocols have been proposed.70,72 Rarely, a
Jarisch-Herxheimer reaction can occur.35 Bacteremia,
which is only rarely detected in CSD, has been treated with 4 weeks
of either azithromycin or doxycycline, occasionally with aminoglycosides.
Hepatosplenic CSD has been treated with rifampin ± gentamicin or
trimethoprim-sulfamethoxazole.40 Treating neuroretinitis
may decrease the incidence and severity of sequelae and a combination
of doxycycline and rifampin for 4 to 6 weeks is recommended for
adults, though a regimen for children younger than 8 years old has
not been defined.70,72 CNS complications are often
treated similarly but for shorter durations, though evidence to support this
is lacking. Corticosteroids have been of benefit anecdotally,73 but
their use should not be considered routinely. It must be emphasized
that the treatment of endocarditis due to B henselae, or
of immunocompromised patients with B henselae infection
including bacillary angiomatosis, peliosis, and bacteremia is not
within the scope of this chapter.
++
++
In healthy individuals, especially in the pediatric age group,
a good prognosis is the rule. Even atypical disease or complications
usually resolve without sequelae. Patience is required because the
infection’s course often spans weeks to months. If
not immunocompromised, lifelong immunity is nearly 100%,
and reinfection or relapse is exceedingly rare. In the immunocompromised,
infection may be life threatening, and immunity may not develop.