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Long-term sequelae of non-A, non-B hepatitis in experimentally infected chimpanzees.

We have observed the development of long-term sequelae in four cases of experimentally induced non-A, non-B (NANB) hepatitis in chimpanzees. These sequelae were characterized by the following manifestations: nonprotection against challenge with autologous infectious plasma following acute disease and subtle histopathological alterations typical of long-lasting viral hepatitis. These manifestations were observed in animals infected with either of two human inocula. Whether or not these inocula represent sources of single or multiple etiologic agents is not known. However, our studies suggest that these inocula share at least one common etiologic agent. Further, these results may represent an atypical chronology of convalescence from viral hepatitis infection. For example, the convalescent stage of a type B hepatitis infection may be expected to occur within 6 to 8 months following exposure, whereas true convalescence in NANB hepatitis may be protracted over several months to several years. Thus, future efforts to identify the causative agent(s) of NANB hepatitis, and efforts to define the immune response in NANB, must take into consideration these studies.

Alanine Transaminase↗

Studies of an outbreak of acute hepatitis A: I. Complement level fluctuation.

An outbreak of hepatitis A occurred in a rural elementary school in Colbert County, Alabama, in October and November 1972. The outbreak was caused by sewage-contaminated drinking water and involved 49 children and 1 adult. Acute and convalescent serum samples were obtained from the hepatitis patients, and from each of 24 unafflicted matched controls at the same time. Strinkingly, the levels of the third and fourth components of complement (C'3 and C'4) were markedly reduced in the acute samples from the sick children but returned to normal in the convalescent ones; the C'3 and C'4 levels in the healthy matched controls were not reduced. In addition, antigen-antibody complexes were found in convalescent sera from some of the sick children. These findings indicate that immune complexes are present in acture hepatitis A and suggest that the techniques for future virus isolation may have to be altered.

Acute Disease↗

Fast-track colonic surgery: status and perspectives.

Multi-modal rehabilitation with an emphasis on preoperative information, reduction of surgical stress responses, optimized dynamic pain relief with continuous epidural analgesia and early mobilization and oral nutrition may reduce hospital stay, morbidity, convalescence, and costs (fast-track surgery). Current results from fast-track colonic surgery suggest that postoperative pulmonary, cardiovascular, and muscle function are improved and body composition preserved as well as a normal oral intake of energy and protein can be achieved. Consequently, hospital stay is reduced to about 2-4 days, with decreased fatigue and need for sleep in the convalescence period. Despite a higher risk for readmissions, overall costs and morbidity seem to be reduced. Existing data from several institutions support the concept of fast-track colonic surgery to improve postoperative organ functions, thereby allowing for early rehabilitation with decreased hospital stay, convalescence, and costs. Further data are needed from multi-national institutions on morbidity, safety, and costs.

Colorectal Surgery↗

Antigenic difference between intracellular and membrane antigens induced by herpesvirus of turkeys.

The difference between intracellular antigen (IA) and membrane antigen (MA) induced by herpesvirus of turkeys (HVT) was examined by immunofluorescence analysis. Convalescent sera from chickens infected with HVT (HVT convalescent serum) and hyperimmune sera from chickens immunized with partially pruified virus (anti-HVT particle serum) or with a major HVT soluble precipitin antigen (anti-common Ag serum) were used as the source of antisera to specify both antigens in these experiments. Absorption of a convalescent serum from HVT-inoculated chicken with IA positive cells, resulted in reduction of their reactivity to IA but not to MA. Differential absorption of the hyperimmune sera by IA positive cells and MA positive cells resulted in reduction of their reactivity to homologous cells but not to heterlogous cells which were used in the absorptions. When the relationship between the levels of anti-IA and anti-MA antibodies was examined by a blocking immunofluorescence test using 38 sera from chickens inoculated with HVT, no correlation was observed (p greater than 0.25). These results provide evidence that MA and IA are antigenically different from each other.

Animals↗

Alteration of T cells and natural killer cells during chickenpox in infancy.

To determine the reasons for the low immune response and the mild morbidity of chickenpox in infancy, we investigated alteration of T cells and natural killer (NK) cells during chickenpox in children < 1 year and > or = 2 years old using flow cytometry. The CD4/CD8 ratio decreased only in the < 1-year-old group from the acute to the convalescent phase (P < 0.05). The CD3-CD16+CD56+ and CD57-CD16+ counts increased in the < 1-year-old group, but those in the > or = 2-year-old group did not increase from the acute to the convalescent phase. The CD3-CD16+CD56+ counts and the CD57-CD16+ counts and percentage were larger in the < 1-year-old group than those in the > or = 2-year-old group (P = 0.001, P = 0.002, and P < 0.05) in the convalescent phase. These results seem to indicate that the low immune response in infancy after chickenpox are related to the small number of CD8 in contrast with CD4 and that increased subsets of NK cells during chickenpox may correlate to the mild morbidity of chickenpox in infancy.

Acute Disease↗

Interleukin-1 secretion by blood monocytes of septic premature infants.

This study examined lipopolysaccharide (LPS) induced in vitro secretion of interleukin-1 (IL-1) by peripheral blood monocytes from pre-term infants with and without sepsis. Thirteen pre-term babies were tested; eight were completely healthy and five suffered from six episodes of sepsis. The latter group was tested both in the acute septic phase and in the convalescent period. IL-1 secretion by monocytes derived from septic pre-term infants was lower, but not significantly different from healthy pre-term infants (7.1 +/- 1.0 U/ml versus 8.1 +/- 0.9 U/ml, respectively). IL-1 secretion by monocytes of eight control full-term babies was in the same range (8.4 +/- 0.6 U/ml). In the convalescent period IL-1 secretion by monocytes from septic pre-term babies increased (9.0 +/- 0.3 U/ml) and was significantly higher than values measured during acute infection (p less than 0.05). Septic premature babies were also found to have higher absolute blood neutrophil concentration (p less than 0.001), but their body temperature did not increase along the infectious stage. The decreased secretion of IL-1 by monocytes from pre-term babies in the acute phase of infection compared to the convalescent period may have contributed to their inability to mount appropriate immunological as well as inflammatory responses. Sepsis promoting IL-1 production in vivo may have limited the monocytes' capacity for LPS stimulated IL-1 synthesis in vitro.

Acute Disease↗

Clinical responses of patients with Kawasaki disease to different brands of intravenous immunoglobulin.

OBJECTIVE: To determine whether different brands of intravenous immunoglobulin (IVIG) administered to children with Kawasaki disease (KD) result in different outcomes. STUDY DESIGN: We analyzed children with KD and divided them into 4 groups according to the brand of IVIG. A coronary artery abnormality (CAA) was defined as having a lumen diameter (inner border to inner border) of > or =3 mm in KD cases <5 years old and > or =4 mm in cases > or =5 years old, and giant aneurysm was defined as a lumen diameter > or =8 mm. Patients were considered nonresponsive to IVIG therapy if fever persisted longer than 2 days after completion of treatment and needed retreatment with IVIG. RESULTS: We collected 437 cases, 29 (6.6%) were nonresponsive, 17 (3.9%) had CAA at convalescence, and 3 (0.7%) had giant aneurysm, 2 of whom had development of myocardial infarcts. Patients receiving Brand C IVIG, prepared with beta-propiolactone, had higher rates (10%, 9/93, P = .01) of CAA at convalescence and nonresponsiveness (13%, 12/93, P = .001); giant aneurysm occurred in 3/93 (3%) receiving Brand C IVIG and in 0/344 who received the other 3 brands (P = .008). CONCLUSIONS: IVIG, prepared with beta-propiolactone, was most significantly associated with nonresponsiveness, CAA at convalescence, and giant aneurysm. Physicians should be cautious when using IVIG prepared with beta-propiolactone or enzyme digestion to treat KD.

Child↗

Circulating D-dimer and thrombomodulin levels in acute febrile phase of measles.

OBJECTIVES: Circulating D-dimer and thrombomodulin (TM) levels are now routinely measured in clinical laboratories. Plasma levels of D-dimer are used as a marker of fibrin formation and degradation, and serum TM is used to assess the state of endothelial cell injuries. While the levels of circulating D-dimer and TM have been investigated in many diseases, to our knowledge they have not been studied in patients with measles. We measured circulating levels of D-dimer in patients with measles to discuss whether fibrin formation and degradation occur and TM whether endothelial injury occur. METHODS: The plasma levels of D-dimer and serum levels of alanine aminotransferase (ALT) and creatinine were measured of 14 adolescent and adult Japanese patients with measles, and the serum or plasma levels of TM of 10 of these 14 patients were measured in the acute febrile phase and convalescent afebrile phase with commercially available kits. RESULTS: Plasma D-dimer levels were significantly higher in the acute febrile phase than in the convalescent afebrile phase in patients with measles, and no significant difference was shown in serum and plasma TM levels between the two phases. Plasma D-dimer levels were not correlated with serum or plasma TM levels in either phase. No significant differences were identified in the serum ALT and creatinine levels between the acute febrile and convalescent afebrile phases, and the levels of plasma D-dimer were not significantly correlated with the serum ALT levels. CONCLUSIONS: Our results indicate that while clot formation and fibrinolysis may tend to occur in patients with the acute febrile phase of measles, there may be little risk that such patients will suffer endothelial injury.

Acute Disease↗

Dobrava virus infection: serological diagnosis and cross-reactions to other hantaviruses.

Recent data have shown that Dobrava (DOB) hantavirus is the cause of severe haemorrhagic fever with renal syndrome (HFRS) in central and eastern Europe. To determine whether serological assays need to be based on the homologous viral antigen rather than on closely related hantavirus antigens, acute and convalescent sera from patients with HFRS collected in former Yugoslavia were examined for IgM and IgG to three hantavirus antigens; DOB, Hantaan (HTN) and Puumala (PUU). Focus reduction neutralization test was included for comparison and confirmation of the enzyme-linked immunosorbent assay (ELISA) results. Although the results showed that the cross-reactivity was high between these three antigens during the acute phase of the disease, one of 155 patients serum samples reacted only in the DOB antigen-based IgM assay. The evaluation of IgG reactivities revealed that a DOB antigen-based IgG ELISA has to be used in sero-epidemiological studies; 7.1% (11/155) of the acute phase/early convalescent sera and 12.5% (2/16) of the late convalescent sera, respectively, reacted only with the homologous DOB antigen.

Convalescence↗

Neonatal back-transport. Cost-effectiveness.

This study examines the cost-effectiveness of returning previously ill neonates to community hospitals after treatment in a tertiary center, a concept known as "back-transport." The authors compared the charges for medical care during convalescence of a group of back-transported infants (BT infants; n = 20) with a similar group of infants who remained in a tertiary center for convalescence (NT infants; n = 20). The total charges for convalescent care (inpatient plus transport charges) for 20 representative BT infants was $61,840, compared with $68,240 for 20 matched NT infants, an average savings of $320 per BT infant. The average daily bed charge and charges for laboratory tests and medications were significantly less for BT infants compared with NT infants, and these reductions offset the transport charges for BT infants. The authors conclude that back transport decreases the charges for medical care for most infants. Therefore, the decision to back-transport an individual infant usually can be based on factors other than cost.

Convalescence↗

Randomized controlled trial of hand-assisted laparoscopic versus open surgical live donor nephrectomy.

BACKGROUND: Laparoscopic live donor nephrectomy for renal transplantation is being performed in increasing numbers with the goals of broadening organ supply while minimizing pain and duration of convalescence for donors. Relative advantages in terms of recovery provided by laparoscopy over standard open surgery have not been rigorously assessed. We hypothesized that laparoscopic as compared with open surgical live donor nephrectomy provides briefer, less intense, and more complete convalescence. METHODS: Of 105 volunteer, adult, potential living-renal donors interested in the laparoscopic approach, 70 were randomly assigned to undergo either hand-assisted laparoscopic or open surgical live donor nephrectomy at a single referral center. Objective data and subjective recovery information obtained with telephone interviews and validated questionnaires administered 2 weeks, 6 weeks, and 6-12 months postoperatively were compared between the 23 laparoscopic and 27 open surgical patients. RESULTS: There was 47% less analgesic use (P=0.004), 35% shorter hospital stay (P=0.0001), 33% more rapid return to nonstrenuous activity (P=0.006), 23% sooner return to work (P=0.037), and 73% less pain 6 weeks postoperatively (P=0.004) in the laparoscopy group. Laparoscopic patients experienced complete recovery sooner (P=0.032) and had fewer long-term residual effects (P=0.0015). CONCLUSIONS: Laparoscopic donor nephrectomy is associated with a briefer, less intense, and more complete convalescence compared with the open surgical approach.

Activities of Daily Living↗

Effect of maternal antibody on IgA antibody response in nasopharyngeal secretion in infants and children during primary respiratory syncytial virus infection.

The IgA antibody response to respiratory syncytial virus (RSV) was determined in nasopharyngeal secretions (NPS) of 22 infants and children infected with RSV group A strains, employing an ELISA. The antibody activity observed during the convalescent phase against whole virus, fusion glycoprotein (F) and large glycoprotein (G) was examined in young infants (under 6 months) and compared with that of older individuals (6 to 16 months). Both groups showed similar degrees of IgA antibody activity to whole virus in NPS; however, older individuals showed a significantly higher activity of IgA F antibody than that of IgA G antibody in the NPS. On the other hand, in the NPS of young infants, IgA F antibody was somewhat suppressed and IgA G antibody activity predominated over that of IgA F. Pre-existing (maternal) serum IgG anti-RSV F antibody activity was higher than that of antibody to G. A significant reverse correlation was observed between the activity of pre-existing serum IgG F antibody and NPS IgA F antibody in the convalescent phase after primary infection with RSV. These observations suggest that maternally derived RSV IgG antibody, which contains abundant anti-F activity, may suppress the development of IgA F antibody response at infection sites in the respiratory tract in young infants during primary RSV infection. These changes may be related to the severity of acute infection and longer convalescence often observed in young infants during RSV infection.

Aging↗

Leukotriene B4 and Kawasaki disease.

The role of LTB4 in Kawasaki disease as a chemo-attractant and immunomodulator is reviewed through our own experience and reports by other investigators. In our experiment using 19 patients, we measured calcium ionophore-stimulated LTB4 synthesis in PMNs obtained in three different stages of the illness (acute, convalescent and recovered phases). LTB4 synthesis was significantly increased in the convalescent phase of the illness. Other investigators showed increased serum-LTB4 concentration in acute as well as convalescent phases, suggesting that LTB4 participated in the inflammatory process of Kawasaki disease as an inflammatory mediator and immunomodulator. However, no difference was found in LTB4 synthetic activity in PMNs in any phases of the illness between the patients with and without coronary lesions, which indicated that LTB4 was not a parameter of coronary aneurysm formation. Therapeutic use of high-dose gamma-globulin showed a tendency to decreased LTB4 synthesis in PMNs, although it is not conclusive.

Child↗

Enterotoxigenic Escherichia coli diarrhea in an endemic area prepares the intestine for an anamnestic immunoglobulin A antitoxin response to oral cholera B subunit vaccination.

We examined whether infection with enterotoxigenic Escherichia coli (ETEC) producing the heat-labile enterotoxin (LT) can prime the gut immune system to respond more efficiently to the immunologically related cholera B subunit component of a recently developed oral B subunit-whole-cell cholera vaccine (B-WCV). Nine Bangladeshi adults who had been hospitalized for watery diarrhea caused by LT-producing ETEC were given a single oral immunization with B-WCV on day 28 after hospital admission. The vaccine preparation used was adjusted to contain a lower-than-usual dose of B subunit, which had been found in previous studies to elicit a significant gut mucosal immunoglobulin A antitoxin response mainly in individuals with previous toxin-specific priming of their gut immune system. For comparison, nine patients convalescing from severe cholera disease and eight healthy subjects with no recent history of either cholera or ETEC infection were given the same oral vaccination with B-WCV. Vaccination in the ETEC convalescents induced an immunoglobulin A antitoxin response in intestinal lavage fluid which was comparable with that in the vaccinated cholera convalescents and superior to that in the vaccinated, previously uninfected controls. By contrast, only the cholera patients responded with anamnestic-type anti-cholera lipopolysaccharide antibody titer rises in the intestine after vaccination. These data support the specificity of the anamnestic anti-cholera toxin response in the ETEC patients after vaccination with cholera B-WCV.

Bacterial Toxins↗

Cellular and humoral immune responses to Borrelia burgdorferi antigens in patients with culture-positive early Lyme disease.

We determined cellular and humoral immune responses to Borrelia burgdorferi lysate and to recombinant flagellin (FlaB), OspC, and OspA in acute- and convalescent-phase samples from 39 culture-positive patients with erythema migrans and in 20 healthy control subjects. During the acute illness, a median of 4 days after the onset of erythema migrans, 51% of the patients had proliferative cellular responses and 72% had antibody responses to at least one of the borrelial antigens tested. During convalescence, at the conclusion of antibiotic therapy, 64% of the patients had proliferative cellular reactivity and 95% had antibody reactivity with at least one of the spirochetal antigens tested. In both acute- and convalescent-phase samples, cellular immune responses were found as frequently to OspA as to OspC and FlaB. Although antibody responses were also frequently seen to OspC and FlaB, only a few patients had marginal antibody reactivity with OspA. The percentage of patients with proliferative responses was similar in those with clinical evidence of localized or disseminated infection, whereas humoral reactivity was found more often in those with disseminated disease. We conclude that cellular and humoral responses to B. burgdorferi antigens are often found among patients with early Lyme disease. In contrast with the other antigens tested, cellular but not humoral reactivity was often found with OspA.

Acute Disease↗

Modified staphylococcal absorption method used for detecting rubella-specific immunoglobin M antibodies during a rubella epidemic.

A recently described method for detecting rubella-specific immunoglobulin M (IgM) antibody based on absorption of IgG by Staphylococcus aureus strain Cowan I has been applied to 198 sera collected during a recent rubella epidemic in Israel. Modification of the original method introduced for the present study includes treatment with 2-mercaptoethanol of antibody remaining after absorption by staphylococci. This treatment confirms that the residual antibody is IgM (sensitive to 2-mercaptoethanol) rather than IgG (2-mercaptoethanol resistant). None of the 67 control patients (seropositive for rubella but without history of recent illness or contact) had specific IgM when tested by this method, though 15 showed some residual antibody after staphylococcal absorption. A total of 125 of 131 rubella convalescents (95%) were positive 4 to 49 days after onset of the clinical symptoms. Six patients had no IgM antibodies when tested by the method described, and all were convalescents tested late in relation to onset of clinical symptoms (beyond 3 weeks). When density gradient centrifugation was applied to clarify some results, 2 of 3 convalescents classified as IgM negative by the staphylococcal absorption method did in fact possess IgM antibody. None of 10 controls tested by density gradient centrifugation was IgM positive. This combination of staphylococcal absorption and 2-mercaptoethanol treatment is recommended as a screening test for selection of IgM positives, in addition to the use of a more sensitive method (such as density gradient centrifugation) on at least some samples classified as IgM negative.

Absorption↗

Time course of lung function changes in atypical pneumonia.

We measured pulmonary function in each of 21 patients suffering from "atypical", non-bacterial pneumonia during the acute illness and during convalescence (two to 18 months) to study the course and the nature of functional impairment at different stages of the disease. In six patients, no aetiological agent was found. An aetiological agent was identified in 15 of the patients: Mycoplasma pneumoniae (seven patients), influenza A (three patients), parainfluenza 3 (one patient), varicella (two patients), Q fever (one patient), coxsackie B3 (one patient). At the time of admission we observed a restrictive pattern in 52%, an obstructive pattern (decreased FEV1/FVC ratio) in 52% abnormalities in distribution of ventilation (abnormal slope of phase 3) in 63%, and abnormalities in gas exchange (increased AaDO2) in 75% of the patients. The frequency of abnormalities in these pulmonary function tests decreased dramatically after two to four weeks and nearly disappeared in most patients during convalescence. The only major residual abnormality was a decreased FEV1/FVC ratio in five subjects, four of whom were smokers. However, when MMEF and V75 were measured at this stage, their average value for all the groups of patients with the exclusion of the Mycoplasma pneumoniae group, was markedly reduced. These data suggest that small airways involvement can be demonstrated during the convalescence of patients recovering from various types of atypical pneumonia other than those caused by Mycoplasma pneumoniae.

Adult↗

Low tissue plasminogen activator relative to plasminogen activator inhibitor-1 as a marker of cardiac complication in children with Kawasaki disease.

To determine whether the fibrinolytic system is related to the occurrence of cardiac complication in Kawasaki disease, we measured tissue plasminogen activator, plasminogen activator inhibitor-1, and related factors in the plasma of children with Kawasaki disease. Patients (mean age, 1.8 years) were classified into patients with cardiac complication (n = 9) and no complication (n = 14) groups echocardiographically. They underwent single, high-dose, intravenous-gamma-globulin infusion therapy. Blood was drawn just before and the day after the single high-dose intravenous gamma-globulin infusion therapy (acute phase), and at early and late convalescent phases. Leukocytosis was normalized immediately after the single, high-dose, intravenous gamma-globulin infusion therapy. C-reactive protein and fibrinogen were increased in the acute phase and normalized by convalescent phases. D-dimer fraction of fibrin degradation products changed in a similar manner. Tissue plasminogen activator and plasminogen activator inhibitor-1 were increased in acute phase. The tissue plasminogen activator/plasminogen activator inhibitor-1 ratio was lower in the complication group than in the no complication group throughout the observation period (0.095 versus 0.208 after single, high-dose, intravenous gamma-globulin infusion therapy, p = 0.006; 0.094 versus 0.183 at late convalescent phase, p = 0.024). A low tissue plasminogen activator/plasminogen activator inhibitor-1 ratio can predict the propensity for cardiac complication, and can help the physician to decide whether additional therapies are necessary in acute phase Kawasaki disease.

Acute Disease↗