Henry H. Balfour

Virus-associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis.

Nineteen patients whose bone marrow smears showed histiocytic hyperplasia with prominent hemophagocytosis were found to have a clinicopathologic syndrome associated with active viral infection. High fever, constitutional symptoms, liver function, and coagulation abnormalities and peripheral blood cytopenias were characteristic findings. Hepatosplenomegaly, lymphadenopathy, bilateral pulmonary infiltrates, and skin rash were often present. Fourteen of the patients were immunosuppressed. Active infection by herpes group viruses was documented in 14 patients and by adenovirus in 1. The bone marrow of most patients also showed decreased granulopoiesis and erythropoiesis with normal to increased numbers of megakaryocytes. Treatment generally consisted of supportive therapy and withdrawal of immunosuppressive drugs. Thirteen patients recovered. Lymph node biopsy and autopsy material showed generalized histiocytic hyperplasia with hemophagocytosis. The relationship of this disorder to familial hemophagocytic reticulosis, familial erythrophagocytic lymphohistiocytosis, histiocytic medullary reticulosis, and malignant histiocytosis is discussed. Immunosuppressive and cytotoxic therapy may be contraindicated in the treatment of this virus‐associated syndrome.

Cytomegalovirus disease in renal allograft recipients: a prospective study of the clinical features, risk factors and impact on renal transplantation.

Fifty-nine renal transplant recipients with overt CMV disease were treated at the University of Minnesota Health Sciences Center between October 1, 1977 and November 15, 1978. In a group of 141 consecutive transplant patients, the incidence of overt CMV disease was 31%. Fifty-three patients (90%) developed clinical manifestations of CMV disease within 4 months of transplantation, and it was during this time period that overt CMV disease was associated with a significantly increased incidence of transplant nephrectomy and death. Fever was the most common presenting symptom (95% of patients), and overt CMV disease was found to be the single most common cause of fever in all hospitalized transplant recipients. Prolonged fever, diffuse pulmonary infiltrates, gastrointestinal bleeding, pancreatitis, transplant nephrectomy and development of other systemic infections were clinical features used to categorize patients according to disease severity. A number of these features were found to be significantly associated with the diagnosis of overt CMV disease. Twelve patients (20%) developed lethal CMV disease characterized by the presence of most of these features, 6 (10%) had severe disease, 9 (15%) had disease of moderate severity and 32 patients (54%) had mild CMV disease with fever being essentially their only clinical finding. Development of secondary systemic infection was most ominous, and occurred before death in 10 of the 12 patients with lethal CMV disease. The only patients to die with serious bacterial, fungal or protozoan infection during the period of this study had concomitant overt CMV disease. Abnormal liver function tests and leukopenia were common, and the degree of abnormality correlated with the severity of CMV disease. Of the multiple factors analyzed for their influence on the risk of developing overt CMV disease, several factors related to the kidney donor (the relationship of the donor to the recipient, HLA matching and CMV serology) appeared to be most important.

Varicella in children with renal transplants

Nineteen of 160 children developed varicella between eight days and 6.4 years following renal transplantation. Eight had severe varicella characterized by prolonged fever and new vesicle formation with rash involving mucous membranes. The severe group had an increased incidence of thrombocytopenia and markedly elevated liver enzyme values. Two patients of this group had bladder paralysis and another died. In three children post-transplant varicella represented a second attack of the disease. Children maintained on azathioprine therapy for three days or more after onset tended to have severe varicella. No graft loss occurred consequent to stopping azathioprine. Children with transplants at risk should have zoster immune plasma or globulin upon exposure, and azathioprine therapy should be stopped at onset of varicella. Corticosteroid therapy should be continued in order to avoid stress-induced Addisonian crisis.

Cytomegalovirus as a risk factor in renal transplantation.

A prospective study of 276 patients that were greater than 12 years old and received transplants between October 1,1977 and September 30, 1979 has been undertaken. Any patient with clinical findings compatible with overt cytomegalovirus (CMV) disease was placed on a “CMV disease diagnostic protocol.” All diagnosed cases of CMV occurring before November 15, 1979 have been analyzed. Eighty patients (29%) had overt CMV disease. Seventy-two (90%) of them contracted CMV within the first 3 months post-transplant. The incidence of overt CMV varied with donor type. Eight percent (4 of 49), 17% (8 of 48), 20% (5 of 25), 40% (46 of 115) and 43% (15 of 35) of HLA-identical (ID) siblings, non-ID siblings, child donor, cadaveric donor, and parental donor, respectively, contracted CMV disease. Overt clinical CMV disease influenced the graft function and patient survival rates significantly (P < 0.01). Several risk factors have been considered as possible indicators of CMV disease. These include age, sex, diabetic status, time of onset of CMV, donor and recipient CMV complement-fixing (CF) and indirect fluorescence (IF) titers. The same variables were analyzed to determine whether they might also predict the severity of the disease. Donor CF is the single most important risk factor. Recipient serology alone was not found to be a significant risk factor but 15 of 27 (56%) persons who had a negative titer and received a kidney from a donor with a positive CF titer contracted overt CMV. Nine of those 15 (60%) had moderate, severe, or lethal illness.

RUBELLA VIRAEMIA AND ANTIBODY RESPONSES AFTER RUBELLA VACCINATION AND REIMMUNISATION

Eleven 4-13 year old schoolgirls, who were seronegative by haemagglutination inhibition (HI) and radioimmunoassay (RIA) tests despite having been given HPV77-DE5 vaccine 3-9 years previously, were revaccinated with RA27/3. They showed evidence of residual immunity since they had accelerated immune responses, little or no rubella-specific IgM, no viraemia, and no vaccine-induced reactions. In contrast, all but one of the five adult women who were primary vaccinees showed a more delayed immune response. Three of four women tested had viraemia and two had vaccine-induced reactions. Enhanced HI and enhanced RIA showed that many of the schoolgirls had antibody before challenge, as did a fifth adult, who also showed an accelerated immune response, yet became viraemic.

Fever in renal transplant recipients: Causes, prognostic significance and changing patterns at the University of Minnesota Hospital

During a three year period in which 433 renal transplants were performed, 194 episodes of fever were documented in allograft recipients hospitalized at the University of Minnesota. Viral infections were responsible for over half of the febrile episodes, and 98 (51 percent) of the fevers were associated with cytomegalovirus (CMV), either occurring alone or in conjunction with allograft rejection or another systemic infection. Bacterial infections, fungal infections and rejection were other important causes of fever, accounting for 14 percent, 5 percent and 13 percent of the febrile episodes, respectively. Most fevers occurred in the first four months after transplantation; although about two thirds of these fevers were due to CMV, only 17 percent of fevers that occurred more than one year after the renal transplant were due to CMV. Bacterial and fungal infections and malignancy were important causes of these fevers. Of the febrile illnesses associated with transplant nephrectomy or death, a majority occurred in patients with CMV disease. Secondary bacterial and/or fungal infections were observed in a large majority of patients with lethal CMV disease. During the third year of this study there was a significant decrease in the proportion of febrile episodes due to CMV.

Jaundice after Renal Allotransplantation

Of 567 patients receiving renal transplantation at the University of Minnesota between October 1967 and October 1975, 22 developed clinical jaundice. Of these 22, nine died with their initial episode of hepatitis, six died within three months of causes associated with liver malfunction, four developed evidence of chronic hepatic failure and only three totally recovered from their illness. Five had clear evidence of Australia antigen positive hepatitis B, four of cytomegalovirus hepatitis, two of herpes hominis hepatitis, one of varicella zoster hepatitis and three of hepatic failure associated with systemic bacterial and/or fungal sepsis. Two of the 22 patients were thought likely to have cytomegalovirus hepatitis though definite proof was absent and in five patients a clear-cut etiology could not be made. In many of these patients the diagnosis was confounded by the previous presence of HBsAg antigen and the frequent occurrence of a previous or concurrent infection with cytomegalovirus. The role of various drugs including azathio-prine, sulfisoxazole, chlorpromazine, acetominophen, etc., could not be established but major roles for these agents in the face of the many viral and bacterial infections present in these patients is doubted. No clear-cut therapy could be established although it appears safe to discontinue azathioprine for longer or shorter periods of time with or without substitution of cyclophosphamide without serious deterioration of renal function. The problem of hepatic failure in transplant patients is still unsolved and will require a prospective study of etiologic agents and sub-clinical hepatic dysfunction in order to establish even the first principles of clinical-pathological correlation.

Zoster immune plasma prophylaxis of varicella: A follow-up report

VARICELLA can be a life-threatening infection in immunocompromised patients. Because a large number of patients with primary or acquired immunodeficiencies are cared for at the University of Minnesota Health Sciences Center, we found it desirable to maintain a supply of zoster immune plasma for attempted prevention of varicelia in such patients. The results of ZIP prophylaxis in 31 of our immunocompromised patients were recently published? The present report expands our study to 50 patients, describes the kinetics of passively transferred varicella-zoster virus antibodies, and provides data suggesting that plasma should be transfused as soon as possible after exposure.

Encephalomyocarditis virus-induced diabetes mellitus treated by islet transplantation

SUMMARY There is considerable evidence that at least some cases of juvenile onset diabetes mellitus in humans are a result of viral infection. Viral-induced diabetes in mice may provide an experimental counterpart more similar to the clinical situation than chemical-induced diabetes. Our experiments in such mice indicate that islet transplantation is effective in ameliorating viral-induced diabetes and is encouraging for ultimate clinical application of islet transplantation to juvenile onset insulin-dependent diabetics. In addition, our results show that islets in ectopic sites outside of the pancreas are resistant to damage induced by primary viral infection. The mechanism of this resistance is obscure and will be the subject of future investigations.

Effect of immunosuppression on humoral and cell-mediated immunity to murine cytomegalovirus.

Summary C57B1/6 mice were immunosuppressed with antilymphocyte globulin and prednisolone around the time of infection with cytomegalovirus (CMV) or from 18 to 30 days after infection. Mice immunosuppressed around the time of CMV infection developed humoral immunity (HI) but not cell-mediated immunity to CMV. The ability of spleen cells to transform to nonspecific mitogens was also depressed in immunosuppressed mice. If mice were immunosuppressed from 18 to 30 days after infection, a time they are known to have CMI to CMV, the CMI disappeared and remained low for the duration of the study (67 days after infection). However, HI was not affected. Transformation of spleen cells to nonspecific mitogens similarly remained low. These studies demonstrate that immunosuppression can abrogate CMI but not HI to CMV.