A young woman with enlarged lymph nodes

2. Which test would provide the greatest diagnostic yield at this point?

• Needle aspiration biopsy of lymph node
• Excisional lymph node biopsy
• Polymerase chain reaction (PCR) testing for HIV
• Antistreptolysin-O (ASO) titer

Because of the persistent enlargement of the patient’s lymph nodes despite several weeks of antibiotic treatment, and because submandibular and supraclavicular nodes were involved, excisional lymph node biopsy would be the best of these choices to evaluate for malignancy. Compared with needle aspiration biopsy, it is the gold standard, preserving the nodal architecture and providing ample tissue for immunostaining and additional studies.

Needle aspiration biopsy is safe, inexpensive, and easy to do and can be useful in situations of limited resources, but it does not reliably distinguish between a reactive and a neoplastic process.¹ Its collection and interpretation are highly variable and personnel-dependent, and its sensitivity for detecting lymphoma is reported to be as low as 7.1% (95% confidence interval 0.9% to 23.5%).²

An acute retroviral syndrome can cause adenopathy, especially before seroconversion is evident, but it is usually associated with an influenza-like illness and monocytosis. Although this patient had no apparent risk factors for HIV, ordering PCR testing for HIV is also an important step when the clinical situation is suggestive. In the absence of an abnormal-appearing oropharynx, tonsillar exudate, or high fever, the pretest probability of streptococcal pharyngitis is low, and an ASO titer is unlikely to be diagnostic in this case.

CASE CONTINUED: BIOPSY PERFORMED

An incisional lymph node biopsy was obtained (Figure 1).

3. Which can confirm the suspected diagnosis?

• Tissue culture
• Test for immunoglobulin (Ig) G and IgM antibodies to Toxoplasma gondii
• Serum PCR testing for T gondii
• T gondii IgG avidity testing

DIAGNOSIS OF TOXOPLASMOSIS

In this patient, acute toxoplasmosis was suspected based on recognition of the morphologic triad seen in Toxoplasma lymphadenitis— ie, follicular hyperplasia, abundance of monocytoid cells, and clusters of epithelioid lymphocytes.^3,4

Detection and measurement of IgM antibodies against T gondii is the most widely used serologic test for acute toxoplasmosis and is often considered the reference standard among the most common commercially available agglutination screening assays. It has a sensitivity between 93.7% and 100% and a specificity of 97.1% to 99.2%.⁵ Confirmation is generally done with enzyme-linked immunoassay or chemiluminescent-based tests, which can detect lower levels of IgG and IgM.⁵

A positive serum IgG confirms seroconversion but by itself cannot distinguish between acute and chronic infection, although it is commonly obtained in conjunction with IgM levels.⁶ Since both IgG and IgM can be elevated months after initial infection, serum IgA and IgE levels can more accurately suggest the timing of infection if clarification is needed.^6,7 In addition, IgG avidity testing can distinguish acute infection from chronic infection: a high avidity index suggests the acute infection occurred at least 3 to 5 months ago, whereas the avidity index may be low or zero if acute infection occurred within the past 4 weeks.⁷ The sensitivity of avidity testing is 91.3% to 94.4%, and the specificity 87.8% to 98.5%.⁷

Serum PCR testing for T gondii is useful when toxoplasmosis is suspected in patients whose immune system may not be able to mount an adequate antibody response or in patients in the hyperacute phase of infection, even before a detectable antibody response can be formed.^8,9 However, because of limitations of equipment, expertise, and overall cost, this method is not universally available. Additionally, blood cultures and PCR testing or tissue culture of pathologic specimens cannot routinely be relied on for diagnosis, as often the burden of microorganisms present in these specimens is low. When positive, culture specimens may yield bradyzoites or tachyzoites, but only after considerable latency of many days to weeks.¹⁰

How people acquire acute toxoplasmosis

T gondii is an obligate intracellular protozoan parasite. Sexual replication of the organism takes place within the intestines of cats (the definitive host), with subsequent excretion of infective oocysts in feces.¹¹ These hardy oocysts can contaminate soil or water supplies and can survive for months, depending on ambient temperature and humidity. Ingestion of oocysts can lead to infection of a variety of mammals, including sheep, pigs, chicken, and cattle.

Infection in humans can occur with consumption of raw or undercooked foods contaminated with oocysts, and inadequate hand-washing and poor kitchen hygiene substantially increase the risk of infection.¹² Activities such as gardening can expose humans to oocysts in contaminated water and soil. In addition, direct contact with cat feces, such as when cleaning the litterbox, is a known exposure risk. Vertical transmission can manifest as congenital toxoplasmosis in a fetus when transmitted from an infected pregnant mother.

Eating raw or undercooked food is considered to be the greatest risk factor for acquired toxoplasmosis and is believed to be responsible for about 50% of all cases.¹² However, in pooled data from 14 case-control studies, no clear risk factor for Toxoplasma infection could be identified in up to 60% of affected people, leading many experts to believe contaminated water may play a larger role in acquisition than previously surmised.¹²

Toxoplasma cysts have a predilection for muscle and neural tissue, resulting in myositis, myocarditis, encephalitis, and chorioretinitis. Severe systemic manifestations are seen in people with impaired T-cell immunity, such as those with HIV infection and acquired immunodeficiency syndrome; or hematologic malignancy; in recipients of solid-organ transplants; or in people taking corticosteroids or cytotoxic drugs. Congenital infection can result in stillbirth, microcephaly, developmental delay, or deafness in the developing fetus and is an important cause of infant morbidity and death worldwide.¹³

Infection in immunocompetent people is usually asymptomatic.¹⁴ However, up to 20% of immunocompetent patients develop symptoms that tend to be nonspecific and include muscle aches and lymphadenopathy, and these are often mistaken for an influenza-like illness.^14,15 Other symptoms include malaise, fevers, night sweats, pharyngitis, abdominal pain, hepatosplenomegaly, maculopapular rash, and atypical lymphocytosis (less than 10% of peripheral blood).¹¹ The most common physical manifestation of acute toxoplasmosis is isolated cervical lymphadenopathy, although any lymph node group can be affected.¹⁴ Lymph nodes are not fixed or matted and generally are neither tender nor suppurative.¹⁶

4. What is the correct treatment strategy for acute toxoplasmosis in this case?

• Symptomatic treatment only
• Trimethoprim 160 mg and sulfamethoxazole 800 mg daily
• Combination of atovaquone and clindamycin
• Combination pyrimethamine, sulfadiazine, and folinic acid