History
Patients with cat scratch 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. [40]
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:
-
Malaise/fatigue (29.4%)
-
Fever (28%): occasionally, CSD may be first evident as a fever of unknown origin [41]
-
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 cat scratch 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. 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 site on the hand of a 16-year-old patient. These lesions had been present for approximately 3 weeks. A cat scratch 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 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.
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 cat scratch 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 cat scratch 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. [42] Adenopathy may not be present. Abdominal pain may be the initial finding, along with fever, in hepatosplenic CSD disease. [43]
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. [44]
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 Cat Scratch 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
-
Fever of unknown origin [41]
Table 2. Clinical Manifestations of Atypical CSD [16, 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. [45] 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. [46, 47, 48, 49] 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. [50] 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. [51] 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, [52] 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 cat scratch 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. [53] 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. [54] 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. [55]
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. [56] 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.
-
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 cat scratch 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 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 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 cat scratch 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 cat scratch 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.
-
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 cat scratch 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.
-
Warthin-Starry stained sections of lymph node showing chains and clusters of organisms. Courtesy of Andrew Margileth, MD.
Tables
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 |
- |
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 |
Ciprofloxacin 500 PO bid |
Case Report 5 adults |
"Dramatic improvement" in a few days; defined as resolution of symptoms (ie, malaise and pain) |
Holley [68] |
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 [69] |
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 [48] |
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 [65] |
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 [64] |
