Steve Kohl

Herpes Simplex Virus Encephalitis in Children

Herpes simplex encephalitis (HSE) is an uncommon disease, yet 25 to 30 per cent of cases involve children. The initial clinical findings are nonspecific (fever, altered mental status), but most cases evolve to demonstrate focal neurologic signs and symptoms. The CSF is abnormal in over 90 per cent of cases. The EEG, CT, and MRI will further help in detecting focal encephalitis. The clinician caring for a child with focal encephalitis should institute broad-spectrum antimicrobial therapy plus acyclovir, pending definitive diagnosis by ancillary tests or brain biopsy, which is positive for HSE 33 to 55 per cent of the time and is diagnostic for other treatable conditions 10 to 20 per cent of the time. Acyclovir is the drug of choice for HSE and substantially reduces mortality and morbidity. The management of HSE in a child requires an experienced team of specialists and laboratory support in a tertiary intensive care setting.

Effect of chemotherapeutic agents on metabolic and bactericidal activity of polymorphonuclear leukocytes

Blood was obtained on 36 occasions from 12 healthy adult volunteers and the polymorphonuclear leukocytes (PMNL) were separated. PMNL hexose monophosphate shunt activity of whole blood and ability of separated cells to phagocytize and kill E. coli were evaluated when the PMNL were incubated with normal pooled sera and sera containing therapeutic concentrations of either 15 cancer chemotherapeutic drugs singly and in combination or 9 antibiotics. Resting and stimulated HMPS activity was significantly (p < 0.025 to p < 0.001) decreased by cyclophosphamide, carmustine (BCNU), high dose prednisone (pred), vinblastine (vinbl) and vincristine (vinc) and significantly (p < 0.025 to p < 0.01) increased by combinations of vinc‐pred, vinc‐predasparaginase, 6‐mercaptopurine (6MP)‐methotrexate (Mtx) and 6MP‐Mtx‐pred when compared to controls. No significant differences in HMPS activity of PMNL were found when exposed to various antimicrobial agents singly or in combination. The killing of E. coli by PMNL was significantly (p < 0.001) decreased when exposed to BCNU, high concentration pred or combinations of 6MP‐Mtx‐pred, 6MP‐Mtx and vinc‐vinbl‐pred but not when exposed to other chemotherapeutic agents. This study shows a disparity in results obtained when evaluating PMNL function by HMPS activity and bactericidal assay. In addition, a functional impairment in PMNL exposed to various antimetabolites occurred at a time when they exhibited normal morphology. Cancer 42:1741–1746, 1978.

Clinical pharmacology of two chloramphenicol preparations in children: sodium succinate (iv) and palmitate (oral) esters

The clinical pharmacology of chloramphenicol was evaluated in 14 children with serious bacterial infections. The children received chloramphenicol sodium succinate intravenously for five to six days at which time orally administered chloramphenicol palmitate was substituted for an additional five to six days of therapy. The mean peak serum chloramphenicol concentration when given iv (28.2 +/- 5.1 micrograms/ml) occurred within one hour after the termination of the 60-minute iv infusion and when given orally (19.3 +/- 2.6 micrograms/ml) occurred two to three hours after ingestion. Differences in serum levels of chloramphenicol after iv compared to oral administration of the same dose could be demonstrated at various time points studied during the dose-response curves; however, the areas under the chloramphenicol curve were not significantly different after iv (140 +/- 116 micrograms/ml/hour) versus oral (95 +/- 26 micrograms/ml/hour) administration. In seven patients who had concomitant serum and CSF chloramphenicol levels determined, a CSF to serum ratio of 23 to 85% occurred. The CSF levels (5.5 to 13 micrograms/ml) were not directly proportional to serum levels. All patients recovered from their infection and no side effects from chloramphenicol were encountered. Administration of chloramphenicol orally in the palmitate form produces serum concentrations and areas under the disappearance curve similar to those achieved after iv administration of the same dose, indicating that the oral route is an effective method of achieving therapeutic concentrations of chloramphenicol in serum.

Yersinia Enterocolitica Infections in Children

Y. enterocolitica has been increasingly associated with a wide range of age-related clinical manifestations in children and adults, including febrile gastroenteritis, pseudoappendicitis, arthritis, sepsis, and focal suppurative disease. Although definite patterns of incidence, prevalence, transmission, and pathophysiology are emerging, much remains to be explained. The alert clinician who notifies his clinical laboratory colleagues that special isolation techniques are required to recover this organism from stool samples, and who submits mesenteric lymph nodes for bacteriologic examination in cases of mesenteric adenitis, will aid attempts to further delineate the significance of this emerging pathogen in the United States. Therapy depends on the form and severity of illness and must be guided by in vitro sensitivity, pending animal and epidemiologic studies.

Herpes simplex virus encephalitis during childhood." Importance of brain biopsy diagnosis

Twelve consecutive pediatric patients 1 day to 11 years of age with suspected herpes simplex virus (HSV) encephalitis underwent brain biopsy. Five were proved to have HSV encephalitis; seven had subdural empyema, malignant glioma, enteroviral encephalitis, (one each), and presumed viral encephalitis, non-HSV (four). Neither epidemiologic, clinical, nor noninvasive laboratory tests were able to help differentiate the two groups of patients. The EEG was more sensitive than the CT scan in demonstrating focal lesions in early HSV encephalitis. In patients with HSV encephalitis, the mean time from hospital admission to appropriate antiviral chemotherapy was 3 days, and the outcome of HSV encephalitis was uniformly poor. In patients with febrile encephalitis-like syndromes with CSF pleocytosis, focal neurologic signs, or other localizing test results (EEG, CT), anticipatory antiviral chemotherapy and brain biopsy are the only hope to prevent the poor outcome associated with HSV encephalitis, to exclude other treatable conditions, and to avoid multiple types of unnecessary empiric therapies.

Cellular cytotoxicity to herpes simplex virus-infected cells of leukocytes from patients with serious burns

Patients with serious burns occasionally are inflicted with unusually severe herpes simplex virus (HSV) infections. Purified monocyte—macrophages (MP), lymphocytes (L), and polymorphonuclear leukocytes (PMNL) from 11 patients with serious burns were studied for their ability to mediate antibody-dependent cellular cytotoxicity (ADCC) and natural killer cytotoxicity (NKC) to HSV-infected target cells in an 18-hr chromium release assay. PMNL-ADCC of the burn patients (29.1 ± 4.1) was significantly higher (P < 0.01) than control subjects (17.2 ± 2.6) in the acute phase immediately following the burn. The patients MP-ADCC (12.3 ± 2.7) was significantly lower (P < 0.01) than control subjects MP-ADCC (32.8 ± 8.2) during the thrid week postburn. There were no significant differences in MP-NKC, L-NKC, and L-ADCC between patients and controls. High PMNL-ADCC was correlated with the high number of immature PMNL in the blood of patients during the acute phase following a serious burn. Low MP-ADCC was noted at the time when severe HSV infection tends to occur in these patients. This may help to explain the burn patients susceptibility to unusually severe HSV illness.

Defects in interleukin-2 stimulation of neonatal natural killer cytotoxicity to herpes simplex virus-infected cells

Natural killer cytotoxicity (NKC) is an important early defense mechanism in viral infections. We determined the ability of interleukin-2 (IL-2), an NKC stimulator, to enhance defective neonatal NKC to virus-infected cells. Human recombinant IL-2-stimulated adult and cord blood NKC to herpes simplex virus-infected cells in a time-dependent and dose-dependent fashion. The highest level of neonatal IL-2-stimulated cytotoxicity approached the level of unstimulated cytotoxicity when adult cells are used. Single-cell experiments suggested that the cord blood defect was due not to decreased adherence but to lysis or recycling defects. IL-2 stimulated adhesion in the presence of antibody but had no stimulatory effect on antibody-dependent cellular cytotoxicity. The relative defects in IL-2 stimulation of neonatal NKC suggest that its lone use as a therapeutic or protective agent against herpes simplex virus infections is unlikely to be successful, and may require concomitant adult cells if NKC is a critical mechanism.

Antibody to cloned HSV glycoproteins B and D plus adult human leukocytes protect neonatal mice from lethal HSV infection.

Antisera produced by HSV infection or following vaccination of guinea pigs with the cloned herpes simplex virus (HSV) glycoproteins gB and gD were compared for in vitro antibody-dependent cellular cytotoxicity (ADCC) activity and for in vivo protection. Antibody from guinea pigs was able to participate in ADCC with human mononuclear cells in vitro, anti-gBgD serum being equivalent to HSV convalescent sera. In vivo, each of the guinea pig sera was able to protect neonatal mice from a fatal HSV-1 infection when given with human mononuclear cells but not when given alone. The anti-gBgD serum was the most effective in vivo, protecting 15 of 17 (88%) neonatal mice when given at a 10(-4) dilution with human mononuclear cells and was the only guinea pig serum protective at a 10(-6) dilution (5 of 7 neonatal mice).

Indomethacin enhancement of human natural killer cytotoxicity to herpes simplex virus infected cells in vitro and in vivo

Indomethacin, a prostaglandin synthetase inhibitor, increased human mononuclear cell (MC) natural killer cytotoxicity (NKC) to herpes simplex virus (HSV) infected cells in vitro at concentrations of 2 X 10(-10)M (p less than .025). Infant mice were significantly (p less than 0.025) protected from a lethal HSV infection by prior injection with a combination of MC and indomethacin (60.7% survival) although neither alone was protective. These results further support the probable in vivo role of NKC in protection against HSV infection, and the critical regulation of NKC by prostaglandins.

Kinetics of human antibody responses to primary genital herpes simplex virus infection.

5 patients with primary genital herpes simplex virus (HSV) infection were studied prospectively for the production of serum antibody reactivity as measured by the virus micro-neutralization test (NT), micro-solid phase radioimmunometric assay (micro-SPRIA), and antibody-dependent cellular-cytotoxic (ADCC) test. ADCC antibody was detected before reactivity measured by either NT or micro-SPRIA in 2 of the patients. A 3rd patient failed to produce neutralizing antibody, whereas specific activity was detected by the other two methods. In 2 other patients a good correlation was observed for development of antibody by all three methods. There were several discordant results in the kinetics of production of antibody detected by these assays, suggesting that not all individuals produce similar types of antiviral antibody.