J. R. Pattison

OUTBREAK OF APLASTIC CRISES IN SICKLE CELL ANAEMIA ASSOCIATED WITH PARVOVIRUS-LIKE AGENT

Since 1952, 112 children with sickle cell anaemia (SCA) in Jamaica have had an aplastic crisis. Outbreaks occurred in 1956, 1960, 1065-67, 1971-73, and 1979-80. Most cases occurred in children under 10 years of age, and an aplastic crisis in a patient over the age of 15 years is rare. There were 38 cases in 1979-80 and stored serum specimens from 28 of these were available for virus studies. Evidence for infection with a parvovirus-like agent was found in 24 of these 28 cases. Viral antigen was detected in 2 patients, both of whom demonstrated seroconversion. Seroconversion during 1980 was detected in a further 7, increasing amounts of antibody during the convalescent period were found in 5, antibody was found in 2 of 4 patients from whom only an acute phase specimen was available and the remaining 10 were antibody positive in the only convalescent phase sample available for testing. Antibody was found in 4 of 94 controls with the SS genotype (in retrospect 2 of these may have had an aplastic crisis) and in 17% of 48 controls with a normal haemoglobin (AA) genotype. The results accord with the possibility that the parvovirus-like agent is the principal cause of aplastic crisis in SCA.

Human parvovirus infection in homozygous sickle cell disease.

We studied the epidemiology of human parvovirus B19 infection in 308 children with homozygous sickle cell (SS) disease and 239 controls with a normal haemoglobin (AA) genotype followed from birth in a cohort study. Annual serum samples identified the time and frequency of B19 infection, which did not differ between SS and AA children, about 40% of each group developing specific IgG by age 15. B19 infection followed an epidemic pattern similar to that observed for aplastic crises; accounted for all 91 aplastic crises that occurred; and was found in an additional 23 SS patients, of whom 10 showed mild haematological changes and 13 no changes. The magnitude or duration of IgG response did not differ between these groups. No patient had 2 attacks of aplasia and no patient nor control had 2 attacks of B19 infection. Following B19 infection, serial specific IgG concentrations remained high after 5 years in only 45% of SS patients, although the rarity of recurrent aplasia suggests lifelong immunity. B19 infection accounts for most if not all aplastic crises in SS disease, but at least 20% of infections do not result in aplasia. An effective vaccine against B19 might make an important contribution to the management of sickle cell disease.

Infection with Parvovirus-like Virus and Aplastic Crisis in Chronic Hemolytic Anemia

From 1980 to 1982 seven adults with chronic hemolytic anemia were admitted to Cook County Hospital, Chicago, with aplastic crisis. Six of these patients had sickle cell anemia, the seventh patient had beta thalassemia intermedia. Virologic studies showed that six patients had acute infection with the human parvovirus-like virus; in the remaining patient the lack of appropriate specimens precluded viral diagnosis. We describe the features of the virus infection and accompanying erythroid aplasia, and discuss the role of parvovirus-like virus as the etiologic agent in the arrest of erythrocyte production.

Glomerulonephritis after human parvovirus infection in homozygous sickle-cell disease

Glomerulonephritis with proteinuria of sufficient degree to manifest the nephrotic syndrome followed aplastic crises induced by human parvovirus (B19) in seven patients with homozygous sickle-cell disease, within 7 days in five patients and 6-7 weeks in two. Segmental proliferative glomerulonephritis was found in all four patients who underwent acute renal biopsies and focal segmental glomerulosclerosis was found in the fifth patient who had a biopsy 4 months later. One patient recovered completely, one died in chronic renal failure after 3 months, and the others had impaired creatinine clearance, four with continuing proteinuria.

Outcome of asymptomatic infection with rubella virus during pregnancy

We have tried to detect prenatal infection in 34 infants whose mothers were re-infected with rubella virus during pregnancy and in six infants whose mothers had primary subclinical rubella during pregnancy. Two methods of assessment were used: first, serum obtained soon after birth was tested for IgM antibody; secondly, serum obtained after the age of 8 months was tested for specific IgG. The 34 women with re-infections had increases in IgG antibody titre but no IgM response. No evidence of prenatal infection was found in 33 of their 34 infants. One infant was found to have IgG antibody at the age of 11 months. This infant was IgM-negative at birth and had a rubelliform rash at the age of 5 1/2 months; it therefore probably contracted post- rather than pre-natal infection. Fetal infection from maternal re-infection during pregnancy is probably rare. The six women with primary subclinical rubella produced both IgG and IgM classes of antibody. Three of their six infants showed serological evidence of intrauterine infection. One, infected when its mother was 8 weeks pregnant, had clinical evidence of congenital rubella. Primary subclinical rubella during pregnancy therefore carries a significant risk of fetal infection. Because of the difference in outcome, great care should be taken to distinguish between primary infection and re-infection when investigating symptomless increases in antibody titre after contact with rubella during pregnancy.

The role of host responses in the recovery of mice from Sendai virus infection.

The antiviral responses in mice to intranasal inoculation with Sendai virus are described. To investigate the relative importance of the humoral, cell-mediated and interferon responses, the pathogenesis of this infection was studied in animals which were immunocompetent, T cell-deprived or immunosuppressed with cyclophosphamide. Treatment with cyclophosphamide converted the mild, self-limiting infection observed in immunocompetent mice into a severe and frequently lethal pneumonic disease. This was associated with an enhanced interferon response but no detectable antibody or cell-mediated immune response. T cell-deprived mice suffer an infection of intermediate severity associated with an increased interferon response, a normal humoral immune response and no cell-mediated immune response. The implications of these results in relation to the role of the antiviral responses in recovery from Sendai virus infection are discussed.

Fetal infection resulting from maternal rubella after the first trimester of pregnancy.

We have tried to measure the incidence of prenatal infection in 304 infants whose mothers had had rubella at various times after the first 12 weeks of pregnancy. Two methods of assessment were used: first, serum obtained soon after birth was tested for specific IgM antibody; secondly, serum obtained after the age of eight months was tested for specific IgG. When maternal rubella occurred 12-16 weeks after the last menstrual period specific IgM antibody was detected in 28 out of 50 infants (56%). The proportion fell progressively to 12% after maternal rubella at 24-28 weeks, rose to 19% after rubella at 28-36 weeks and then to 58% when the illness occurred during the last month of pregnancy. In all, IgM antibody was detected in 77 out of 260 infants (29%). The fetus can thus be infected at any time during the second and third trimesters of pregnancy, but the risk varies at different stages.The figures for the prevalence of IgG antibody were greater throughout, because some infants had IgG who had previously lacked specific IgM. After maternal rubella at 12-16 weeks IgG antibody persisted in 22 out of 31 infants (71%). The proportion fell to 28% after rubella at 24-28 weeks and then increased progressively to 94% after rubella during the last month. In all, IgG antibody persisted in 94 out of 190 infants (49%). The true rate of fetal infection probably lies between the rates estimated from the presence of IgM antibody and the subsequent prevalence of IgG.Infants whose mothers had rubella at any time during pregnancy should be examined regularly for possible evidence of damage.

Comparison of methods for detecting specific IgM antibody in infants with congenital rubella.

Serum specimens from 14 infants with congenital rubella were examined for specific IgM antibody by six different methods. IgM-containing fractions were separated either by sucrose density-gradient centrifugation or by gel filtration through Sephadex G-200, and were then tested by the indirect immunofluorescence technique and by the haemagglutination-inhibition (HI) test (long-and short-incubation methods). Immunofluorescence staining of density-gradient fractions detected specific IgM in all 14 infants. The HI test (long method), applied to density-gradient fractions, was almost as sensitive, detecting antibody in 13 infants; the short method was less sensitive. The gel-filtration technique proved to be generally less satisfactory than sucrose density-gradient centrifugation. Evidence was obtained for the occurrence of as yet unclassified non-specific inhibitors in the serum of some infants. These inhibitors were deposited with the IgM on sucrose-density gradients and they could have been mistaken for rubella-specific IgM antibody, particularly in the HI test (long method).

Outcome of Asymptomatic Infection with Rubella Virus during Pregnancy

We have tried to detect prenatal infection in 34 infants whose mothers were re-infected with rubella virus during pregnancy and in six infants whose mothers had primary subclinical rubella during pregnancy. Two methods of assessment were used: first, serum obtained soon after birth was tested for IgM antibody; secondly, serum obtained after the age of 8 months was tested for specific IgG. The 34 women with re-infections had increases in IgG antibody titre but no IgM response. No evidence of prenatal infection was found in 33 of their 34 infants. One infant was found to have IgG antibody at the age of 11 months. This infant was IgM-negative at birth and had a rubelliform rash at the age of 5 1/2 months; it therefore probably contracted post- rather than pre-natal infection. Fetal infection from maternal re-infection during pregnancy is probably rare. The six women with primary subclinical rubella produced both IgG and IgM classes of antibody. Three of their six infants showed serological evidence of intrauterine infection. One, infected when its mother was 8 weeks pregnant, had clinical evidence of congenital rubella. Primary subclinical rubella during pregnancy therefore carries a significant risk of fetal infection. Because of the difference in outcome, great care should be taken to distinguish between primary infection and re-infection when investigating symptomless increases in antibody titre after contact with rubella during pregnancy.