THE JOURNAL OF INFECTIOUS DISEASES • VOL. 140, NO.6. • DECEMBER 1979 © 1979 by The University of Chicago. 0022-1899/79/4006-0005$00.75

Effect of Specific Antibodies on Chronic Echovirus Type 5 Encephalitis in a Patient with Hypogammaglobulinemia L. S. Weiner, J. T. Howell, M. P. Langford, G. J. Stanton, S. Baron, R. M. Goldblum, R. A. Lord, and A. S. Goldman

From the Departments of Pediatrics, Microbiology, and Human Biological Chemistry and Genetics, The University of Texas Medical Branch, Galveston, Texas

Serious viral infections have emerged as a complication in immunosuppressed patients. Indeed, patients with deficiencies of humoral or cell-mediated immunity (CMI) are more susceptible to certain viral infections [1-4], including those caused by the enteroviruses [5-13], than are patients who are not immunosuppressed. In particular, chronic echovirus infections of the central nervous system (CNS) have become evident in patients with hypogammaglobulinemia [10-13]. It has been assumed that enteroviral infections in these individuals are due to a lack of specific antibodies. If that assumption is correct, then administration of specific antibodies might control the infection. Bardelas et al. [12] and Webster et al. [13] administered plasma containing virus-specific antibodies to hypogammaglobulinemic patients who had disseminated echovirus infections, but the treatment had

no demonstrable effects. However, low levels of specific antibodies were infused, and there was limited information concerning the quantitation of virus or specific antibody in their investigations. Recently, we systematically examined the effects of high quantities of specific antibodies in an individual with x-linked hypogammaglobulinemia and chronic echovirus type 5 (echo 5) encephalitis. Although the subject died as a result of a complication of the infection, infusions of human plasma containing high titers of specific antibodies to the echovirus led to detectable levels of antibodies to the virus in the CSF and caused a marked reduction in the concentration of virus in the CSF and blood. Case Report

The patient was first evaluated at age three years because of repeated infections of the respiratory tract. X-linked hypogammaglobulinemia was diagnosed. He was treated with pooled human gammaglobulin (HGG) (0.8 ml/kg every three weeks), but his clinical course was marked by repeated respiratory and intestinal tract infections, rheumatoid-like arthritis, and a chronic myositis. A bilateral, progressive sensorineural hearing loss and transient ataxia developed in 1974 and in 1975, respectively. In January 1976, headaches, blurred vision, sore throat, fever, drowsiness, ataxia, and a left-sided ptosis appeared. Physical examination revealed hepatomegaly, atrophic skin over the legs, and focal CNS signs that suggested a

Received for publication January 8, 1979, and in revised form April 26, 1979. This work was supported in part by James W. McLaughlin Postdoctoral Fellowships awarded to L. S. Weiner and J. T. Howell; by a James W. McLaughlin Predoctoral Fellowship awarded to M. P. Langford; by research grant no. DHEW RR-00073-14 from the General Clinical Research Centers Branch, Division of Research Facilities and Resources, National Institutes of Health; and by Public Health Research grant no. EY 01715-03 from the National Eye Institute. We thank Carol Cleghorn, Mary Douglas, Maureen O'Donohoe, and Beth Rudloff for technical assistance and the staff of the Clinical Research Center. Please address requests for reprints to Dr. A. S. Goldman, Department of Pediatrics, Child Health Center No. 235, The University of Texas Medical Branch, Galveston, Texas 77550.

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The effects of specific antibodies in chronic echovirus type 5 (echo 5) encephalitis were investigated in a patient with x-linked hypogammaglobulinemia. Virus was detected in cerebrospinal fluid (CSF) and blood despite treatment with commercial human gammaglobulin that contained low titers of antibodies to echo 5 (0.6 x 104 units per injection). Virus disappeared from blood and CSF when plasma containing high concentrations of antibodies (total dose, 1-4 x 104 units/kg) was administered intravenously. Maximal inhibition of virus was achieved in culture and in the patient's CSF when the titer of antibody to echo 5 in CSF was ~16 units/ml. Although the patient died, hyperimmune plasma improved the neurologic status and eliminated detectable virus from the blood and CSF.

Echo Encephalitis in Hypogammaglobulinemia

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brain stem lesion. A panhypogammaglobulinemia and a paucity of circulating B cells were found. An electroencephalogram (EEG) and a computerized axial tomogram (CAT) scan were normal. The CSF contained 513 lymphocytes and 56 monocytes/mm 3 , low levels of glucose (24 mg/loo m}) (the level of blood glucose was determined simultaneously, 80 mg/ 100 ml), and elevated levels of armacroglobulin (14 mg/loo ml), but no detectable immunoglobulins. Interferon (IF) (10 units/ ml) and echo 5 were detectable in the CSF.

Immunoglobulin and armacroglobulin measurements. IgG, IgA, IgM, and armacroglobulin in serum and CSF were measured by single radial immunodiffusion [14] with use of commercial plates and standards (Calbiochem-Behring, La Jolla, Calif.). Virus isolation and quantitation. Venous blood, CSF, urine, feces, saliva, liver, and skeletal muscle biopsy specimens were assayed for virus in microtiter plate cultures of human skin muscle fibroblasts [15]. Virus titers are expressed as loglo TCIDso/ml.

Results

Pre-experimental therapy period. In January 1977, echo 5 was isolated (figure 1) from the pa-

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Figure 1. Levels of echovirus type 5 in the cerebrospinal fluid (CSF) (-- • --) and blood (- - - 0 - - -) of a hypogammaglobulinemic patient. Levels were determined before and after the administration of pooled human gammaglobulin (HGG) (*), pooled HGG containing 0.6 x 104 units of specific antibody ( c::::J ), high-titered human plasma (~), and human plasma containing no antibody to echovirus type 5 (~).

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Materials and Methods

Neutralizing antibodies. Neutralizing antibodies to echo 5 and poliovirus type 2 (polio 2) were measured in WISH (Wistar Institute Sarah Hayflick) cells by standard methods [16] with use of WISH cell-adapted echo 5 and polio 2. One antibody unit was defined as the amount that neutralized 30 TCIDso of echo 5 or polio 2. Plasma donors. Samples of plasma obtained from consenting blood bank donors who had a titer of antibody to echo 5 of>100 units [16] were plasmapheresed. The high-titered plasma will be referred to as hyperimmune plasma. IF determinations. CSF and sera were assayed for IF in human WISH cells by means of CPE reduction microassay [17] and Sindbis virus as the challenge virus. Samples were assayed directly without removal of wild-type virus, since preliminary studies showed that wild-type virus did not grow well or interfere with replication of Sindbis virus in WISH cells. The titers are reported in NIH reference units.

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that high levels of specific antibodies could be attained in the CSF. The therapeutic action of large amounts of antibody was first manifested by the sharp decrease in CSF virus and the disappearance of viremia following the administration of hyperimmune plasma. Antibody neutralization of extracellular virus and inhibition of viral spread to uninfected cells was suggested by the finding that IF was found in CSF only when virus was detectable and antibody to echo 5 was absent. In addition, the decrease of virus in CSF was related to the amount of antibody infused and to the concentration of specific antibody in the CSF (figures 1 and 2). In further trials, echo 5 became undetectable in CSF when high quantities of specific antibodies were administered (figure 1). An inverse linear relationship was found between echo 5 and specific antibody in CSF. Maximal inhibition was achieved with a concentration of ~ 16 antibody units/ml (figure 4), an amount similar to that found to inhibit virus in vitro (figure 3). Although positive effects of hyperimmune plasma were evident, the patient died after a cerebral hemorrhage. It is not known whether this was a complication of antibody therapy or chronic vasculitis associated with the virus infection. Unfortunately, immunologic or virologic investigations

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Figure 4. Comparison of the concentration of echovirus type 5 and antibodies to the virus in cerebrospinal fluid (CSF) of a hypogammaglobulinemic patient. If the data point at 48 units/ml is equated with the data point at 16 units/ml, an inverse relationship is evident (r = - 0.768; P