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. [57] 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. [58]
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. [59]
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. [14] 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. 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 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. [60] 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. [59]
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 cat scratch 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. [14] The specificity of staining is improved with the use of immunohistochemical assay. [61]
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. [28]
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.
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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.
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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.
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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.
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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.
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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.
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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.
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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] |
