P. B. A. Kernoff

Serial CD4 lymphocyte counts and development of AIDS.

Low CD4 lymphocyte counts are associated with increased risk of progression to AIDS in human immunodeficiency virus (HIV) infection. We investigated the extent to which the timing of progression to AIDS can be explained solely in terms of decline of the CD4 lymphocyte count in 111 haemophiliacs followed for up to 11 years since infection with HIV. A median of 10 CD4 lymphocyte counts were made per patient. By applying a simple linear model for the decline in CD4 lymphocyte counts over time, we estimated the date of development of AIDS in 96 patients who had at least 5 determinations. 84% (81 of 96) of patients were correctly classified as to development of AIDS before Jan 1, 1990 (p less than 0.0001), with this model. The results suggest that differences in the time at which patients with HIV will progress to AIDS can largely be explained by differences in rates of decline of CD4 lymphocyte counts.

CYTOMEGALOVIRUS INFECTION AND PROGRESSION TOWARDS AIDS IN HAEMOPHILIACS WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION

To examine whether cytomegalovirus (CMV) infection could accelerate progression of human immunodeficiency virus (HIV) infection to AIDS, serological studies were done on 108 HIV-infected haemophiliacs. In the 1.3-9 years from time of first recognised HIV seroconversion, the age-adjusted risk of CDC group IV disease in CMV-seropositive patients was 2.5 times that in CMV-seronegative patients. CMV-seropositive patients were also more likely to have detectable p24 antigenaemia. Survival analysis showed that CMV-seropositive patients were at greater risk of HIV disease than CMV-seronegative patients from about 2 years after HIV seroconversion. Thus CMV infection is associated with a more rapid progression to HIV disease.

Inheritance and bleeding in factor XI deficiency

A study of 20 Jewish and four non‐Jewish kindreds transmitting factor XI deficiency (164 individuals) confirmed inheritance to be autosomal with severe deficiency in homozygotes (mean factor XI level 3.8 u/dl, SD 2.91) and partial deficiency in heterozygotes (mean factor XI level 57 u/dl, SD 10.42; normal mean factor XI level 96 u/dl, SD 11.6). The probability of an individual being heterozygous can be predicted from the factor XI level using a graph derived from this data. The accuracy is increased by including the prior probability derived from the pedigree. A high frequency of heterozygote to heterozygote mating was observed in the Jewish families consistent with an estimated gene frequency of 13.4% in this racial group. The relationship between factor XI level and bleeding tendency is poor; a third of heterozygotes had bled excessively after surgery, including six with factor XI levels above 50 u/dl, showing this condition to have clear signs of expression in heterozygotes. The lower limit of the normal range (2 SDs from the mean) was found to be 72 u/dl.

Response to infusions of polyelectrolyte fractionated human factor VIII concentrate in human haemophilia A and von Willebrand's disease

Summary. Factor VIII was purified from cryoprecipitate by ion exchange chromatography on solid phase polyelectrolyte E‐5 (PE‐E5). The product was highly purified (3.5 u VIII: C/mg protein) compared to conventional concentrate (0.3 u VIII: C/mg protein) with low fibrinogen, low isoagglutinin titre, and a ratio of factor VIII coagulant activity (VIII: C) to factor VIII related antigen (VIIIR: Ag) of 16:1.

High risk of non-A non-B hepatitis after a first exposure to volunteer or commercial clotting factor concentrates: effects of prophylactic immune serum globulin

After a first exposure to factor VIII concentrates, 9/9 British patients treated with U.S.A.‐derived commercial products, and 10/12 treated with British volunteer (NHS) products, developed acute non‐A, non‐B (NANB) hepatitis. Hepatitis following commercial products was more severe, and of shorter incubation. High previous exposure to NHS blood products seemed to prevent NHS but not commercial factor VIII‐induced hepatitis; the latter was also not attenuated by administration of U.S.A.‐derived commercial immune serum globulin (ISG). After a first exposure to NHS factor IX concentrates without ISG, 4/4 patients developed short incubation NANB hepatitis; one also contracted prolonged incubation hepatitis B. One patient treated with ISG and factor IX of proven infectivity did not develop hepatitis, suggesting protection by ISG. Observed differences between concentrates might be attributable to their content of different NANB agents, but dose‐related effects could provide alternative explanations. This data provides a basis for comparative assessment of new products of possible reduced infectivity in only small numbers of patients.

HYPOTHYROIDISM AS A CAUSE OF ACQUIRED VON WDLLEBRAND'S DISEASE

Three patients with bleeding tendency who met the criteria for type 1 von Willebrands disease are described. In two patients, hypothyroidism was suspected and confirmed at presentation, and in the third hypothyroidism became apparent 4 years later. In all three, the history and clinical course after treatment with thyroxine indicated acquired von Willebrands disease secondary to hypothyroidism. The possibility of hypothyroidism should be considered in patients presenting with von Willebrands disease.

Reduced risk of non-A, non-B hepatitis after a first exposure to ‘wet heated’factor VIII concentrate

The risk of post‐infusion non‐A, non‐B hepatitis (NANBH) in patients receiving a first exposure to unheated or conventionally ‘dry heated’factor VIII concentrates approaches 100%. implying invariable contamination of these products. Amongst 18 patients who received a first treatment with a ‘wet heated’commercial concentrate, five (28%) developed asymptomatic NANBH, suggesting a more efficient inactivation of NANB agent(s) by this process. 2/9 (22%) of the batches of concentrate used in the study were implicated in NANBH transmission. One of these two batches. responsible for NANBH in four patients, had been prepared from a plasma pool containing an unusually large proportion of donations with high alanine aminotransferase (ALT) levels. A resulting high level of viral contamination in this batch may have been sufficient to override the effects of the sterilization process. All patients remained anti‐HIV seronegative at 17–28 months of follow‐up.

Interferon therapy for chronic non-A non-B and chronic delta liver disease in haemophilia.

Summary. The case histories of a carrier of haemophilia A with chronic post transfusion non‐A non‐B hepatitis and a severe haemophiliac with chronic delta hepatitis are described. Therapy with lymphoblastoid alpha interferon resulted in improvement of NANB and HDV related chronic hepatitis and resolution of HIV related thrombocytopenia. Interferon may modulate replication of more than one transfusion transmitted virus in the haemophiliac.

Relationships between blood product exposure and immunological abnormalities in English haemophiliacs.

Amongst 160 English haemophiliacs treated with clotting factor concentrates, abnormalities of T lymphocyte subset distribution (characterized by low T4/T8 ratios and high total T8 counts), low in vitro phytohaemagglutinin stimulation and raised serum IgG levels, were more common in patients with haemophilia A than B, in patients who had received heavier blood product exposure, and in adults rather than children. A slight reduction in lymphocyte and platelet counts was found in 26% and 17% of patients. In the sample of patients tested, serum α1‐thymosin levels were often raised, but β2‐microglobulin levels were usually normal. Fractionation procedures used to prepare clotting factor concentrates, and the amounts of concentrate used, are more likely to be causally related to these immunological abnormalities than the origins of source donor plasmas.

Interactions between hepatotropic viruses in patients with haemophilia.

Infections with the hepatotropic viruses non-A, non-B (NANB), hepatitis B (HBV) and delta agent (HDV) are described in two patients with haemophilia. The first patient illustrates the phenomenon of interference following a simultaneous exposure to NANB and HBV. The second patient, a carrier of hepatitis B surface antigen (HBsAg), acquired superinfection with HDV which resulted in acute hepatitis progressing to chronic hepatitis. Liver disease seen in multitransfused haemophiliacs may be significantly different to that seen in other patients. As a consequence of the infusion of blood clotting factor concentrates, these patients become the site of complex viral interactions.