CASE 31

RR, a 17-year-old woman who was previously well, has been admitted to the hospital because of fever, rash, generalized fatigue, and acute pain in the left eye. In the last 2 months she has lost 12 kg in weight and reports an intermittent fever with fatigue of the same duration. She has had multiple sexual partners and a therapeutic abortion at 14 years of age. There has been no recent travel, and a tuberculosis skin test is negative (with positive control). She appears ill, has marked conjunctival infection, a tender sclera with palpation, and left retinal detachment with some peri-orbital swelling. Fundoscopic/ophthalmoscopic examination (of the optic disc, blood vessels, and retina) is otherwise normal. The remainder of the ears, nose, and throat examination is unremarkable, although she does have prominent nontender cervical nodes. There is also swelling of the inguinal nodes, a macular rash (small, flat spots) on the thigh, and a faint cardiac murmur in the upper chest.

An HIV (ELISA) and a syphilis (VDRL) test were ordered immediately, as was a urine and blood screen culture, and chest radiograph. HIV tests were negative, but a serologic test for syphilis was positive, although a hemagglutination test for Treponema pallidum was negative (i.e., a “false positive” syphilis test was seen). Urine showed 2+ (30 mg/dL) protein, some red blood cells, and some hyaline casts (generally reflecting inflammatory changes in the upper urinary tract, including the kidney). Blood screen indicated that she was moderately anemic (hemoglobin 80% of normal; see Appendix for reference value), with a lymphopenia (lymphocyte counts about 20% of normal) and low platelets. The chest radiograph was normal. A bone marrow aspirate with smear was performed. However, there was no evidence for lymphoma or leukemia, Hodgkin’s disease, malignant histiocytosis (resident macrophages in connective tissue), or other immunolymphoproliferative disorders. Computed tomography (CT) showed swelling of the soft tissues around the left eye and evidence for cerebral atrophy. Blood cultures remained negative throughout hospitalization.

RECOMMENDED APPROACH

Implications/Analysis of Family History

No family history is provided. See Cases 18 and 22 for genetics of this disorder.

Implications/Analysis of Clinical History

This presentation is consistent with multiple disorders; and in attempting to exclude them, it is essential to be judicious in choice of tests. The picture seems to be one of an acute disorder, and our diagnostic decision tree should keep this in mind.

Implications/Analysis of Laboratory Investigation

Ruling Out Infection

Early testing ruled out the probability of acute or chronic infectious disorders as explanation for these symptoms in that the chest radiograph is normal, blood cultures are negative, as are the tests for HIV and syphilis. Although the VDRL assay, the screening test for syphilis, was positive, the confirmatory test was negative. The VDRL assay detects anticardiolipid antibodies. Because these antibodies may be present in patients with some viral, bacterial, and parasitic infections, and in some autoimmune disorders, there is a high incidence of false-positive findings. Therefore, a confirmatory test that detects antibodies specific for antigens expressed on Treponema pallidum (the causative agent of syphilis) is required. The confirmatory test was negative, indicating that RR did not have syphilis, but she does have anticardiolipin antibodies, and we must take this into consideration when determining a diagnosis.

Ruling Out Malignancy

The likelihood of a malignancy (lymphoma, leukemia, Hodgkin’s disease, malignant histiocytosis, or other lymphoproliferative disorders) has lessened at this time in that the chest radiograph is normal and the white blood cell count is reduced (not elevated). As well, the bone marrow smear, which provides (1) a leukocyte estimate, (2) leukocyte differential, (3) the presence of abnormal cells (e.g., Reed-Sternberg cells in Hodgkin’s disease), (4) as well as erythrocyte, and (5) platelet morphology, was normal.

Anemia, Proteinuria, and Hyaline Casts

RR is moderately anemic, but a number of mechanisms can lead to anemia (e.g., trauma, autoanti-bodies, infections, iron deficiency, drug associated). Urinalysis revealed proteins, red blood cells, and hyaline casts. Hyaline casts consist of material shed from renal tubules but retain the shape of the tubule. Hyaline casts are made of gelled protein and are translucent.

The presence of protein, red blood cells, and hyaline casts in the urine is an indication that the kidneys are not functioning normally. Renal problems can develop as a result of immune complex deposition in the glomeruli. Because we have already ruled out an acute or chronic infection, as well as a malignancy, these could not be the source of antigen and so we should be focusing our attention to autoimmune disorders in which immune complexes contribute to the pathology. Circulating immune complexes could also trigger inflammatory reactions that result in swelling of soft tissues around the left eye and cerebral atrophy (as shown on CT).

Rheumatologic Disorders as Possibilities

Our focus has instead switched to the likelihood of a rheumatologic disorder as the primary diagnosis. The spondylarthropathies such as Reiter’s syndrome or Crohn’s disease are unlikely, given the lack of evidence for musculoskeletal symptoms (prominent in Reiter’s disease, as is keratitis and iritis, not scleritis) or gastrointestinal symptoms (for Crohn’s disease). Sarcoidosis might also explain the scleritis and renal involvement but is less likely in the absence of lung disease and arthritis. Behçet’s disease, a chronic inflammatory disorder in which HLA-B51 is risk factor, is associated with ocular inflammation but generally presents as mucosal ulceration (absent in this patient). Rheumatoid arthritis is unlikely in the absence of any joint symptoms.

Vasculitis is an inflammation of the blood vessels that results from narrowing of the inflamed vessels and, hence, insufficient blood flow to the affected organ (Fig. 31-1). Therefore, manifestations or symptoms depend on the particular vessels involved. Polyarteritis nodosa, a multisystemic disease that often involves the skin, nerves, heart, gut, and kidneys might be considered except that most cases occur in 40- to 60-year-old patients. Dermatomyositis might be considered, bearing in mind the vague symptoms and the rash. Blood work to eliminate muscle inflammation essentially removes the latter from consideration.

FIGURE 31-1 Necrotic digital ulceration in a patient with vasculitis (immune complex–mediated).

(From Goldman L, Ausiello D: Cecil Textbook of Medicine, 22nd ed. Philadelphia, Saunders, 2004.)

Wegener’s granulomatosis, a granulomatous vasculitis that can present with scleritis, rash, and renal involvement, is certainly a consideration. It affects both men and women of all ages. Typically, these patients produce high titers of anti-neutrophilic cytoplasmic antibodies (ANCA), and an ELISA could be ordered to rule out this possibility, but the false-positive syphilis test is not readily explained by vasculitis.

Immune Complex Disorder

High on the list of possibilities is systemic lupus erythematosus (SLE). Immune complex deposition in different tissues would explain the results of the urinalysis, CT, and false-positive VDRL assay. As well, lymphopenia, thrombocytopenia, cardiac signs (the murmur referred to earlier), and the rash are consistent with a diagnosis of SLE. The rash results from blood leaking out of damaged blood vessels during the inflammatory processes. The cerebral atrophy is striking in one so young, but it could represent lupus cerebritis, an inflammation of the brain. Therefore, tests to determine the ANA and anti-DNA titer, as well as a biopsy of the rash were ordered (see Additional Laboratory Tests).

Additional Laboratory Tests

A serologic test for ANA was performed (positive at a titer of 1:2000). Antibodies to double-stranded DNA were detected at high titer (1:640), and complement C3 and C4 were low, as were total serum complement levels (see Case 11). Biopsy of the rash showed features typical of leukocytoclastic (small vessel) vasculitis.