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Appendicitis: Evolving Tools to Diagnose a Classic Disease

Michael S. Singer, M.D., Ph.D.
Contributing Editor

Appendicitis is a common, potentially lethal condition that affects 7% of individuals sometime in their lives. The condition occurs when the appendix, a blind pouch of intestine at the proximal colon, becomes obstructed by mucus, stool, or lymphatic tissue. Infection ensues, which can rapidly evolve to perforation and sepsis. The risk of these complications, already elevated for children and those over 50, rises as appendectomy is delayed. To compound the problem, numerous diseases mimic appendicitis, and it is often difficult to rule it out based on clinical presentation. This is due to well-known variance in history and physical exam. For example, the classic symptoms of abdominal pain, nausea, and loss of appetite have minimal if any predictive value for appendicitis versus other abdominal conditions. Clinicians fail to appreciate appendicitis on presentation in 25-30% of children.

Uncertainty often remains even after physical exam. The classic finding of right lower quadrant tenderness is present in some 96% of appendicitis patients but also in many other conditions. No feature on physical exam has been proven to rule out appendicitis definitively. Fortunately, a number of laboratory and imaging modalities, some new and sophisticated, can improve levels of clinical confidence. Ideally, these tools should provide optimal positive predictive value to facilitate early appendectomy, all in an effort to reduce mortality rates (which can reach 1%). They should also provide optimal ,i>negative predictive value to rule out appendicitis with confidence and avoid unnecessary surgery.

Clinicians invariably order laboratory studies in cases of suspected appendicitis, where an elevated white blood cell count (WBC) is a classic but nonspecific feature. Only 80-85% of patients with appendicitis, however, have a WBC over 10K. A study with excellent sensitivity is serum C-reactive protein (CRP), a marker of systemic inflammation produced by liver cells. CRP is elevated in many different diseases, but when appendicitis is suspected, a normal CRP has a negative predictive value near 100%. Antibody-based assays are available to determine CRP levels in well under an hour.

Computed tomography (CT) of the abdomen is a mainstay and is particularly helpful if the appendix is visible on the scan. With oral or rectal contrast (with or without intravenous contrast), sensitivity and specificity can both approach 98%. Helical CT, which has finer resolution and shorter acquisition times, has improved test quality and made it more practical for patients who cannot remain still. Another important benefit of CT is that it can reveal diseases other than appendicitis. Unfavorable aspects of CT remain the radiation dose and need for contrast.

Another option is ultrasound, which may be particularly useful for children and has the benefit of no radiation. The test is also readily available. As tradeoffs, ultrasound is less sensitive and specific compared to CT. The test is also operator-dependent.

A new tool to detect appendicitis is the in vivo tracer NeutroSpec (fanolesomab; Mallinckrodt). This mouse antibody binds human CD15, a surface marker for neutrophils as well as eosinophils and some monocytes. When introduced into the blood stream, the antibody attaches to neutrophils, which then travel to the infected appendix. The antibody may also bind portions of neutrophils already at the appendix. Technetium-99m, supplied as a pertechnate and attached to the antibody, serves as a radiolabel to detect antibody as it concentrates in the appendix. This radionuclide has a half-life of approximately 6 hours, and the safety of the radiation dose is well established. A special camera used in nuclear medicine suites can detect the radiolabel and any hyperactivity in the appendix.

Neut roSpec is FDA-approved for equivocal appendicitis in patients five years and older. The test is a valuable advance over radiolabeled leukocytes, which work in a similar fashion but require the time- and labor-intensive process of collecting, labeling, and reinfusing the patients own white blood cells.

The only side effects of NeutroSpec in preclinical trials were mild flushing and shortness of breath (please see complete Prescribing Information before use). The manufacturers points out that, as with any intravenous tracer, allergic reactions may occur. Intravenous administration of a mouse antibody also raises the possibility of human anti-mouse antibodies (HAMA). In a study of 30 healthy volunteers who received two doses of fanolesomab, 5 patients (16.7%) developed such antibodies, but they had no detectable clinical effects.

NeutroSpec technology may also blaze the trail for in vivo tracers in other conditions such as osteomyelitis and fever of unknown origin (FUO). Meanwhile, clinicians have new options to deal with the classic yet diagnostically challenging entity of appendicitis.

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