A 13-month-old Caucasian female presented with erythema, swelling, and pain of the left periorbit... more A 13-month-old Caucasian female presented with erythema, swelling, and pain of the left periorbital region. On admission, her vital signs were normal, and complete blood count did not reveal abnormalities. Blood and eye cultures were collected. On physical examination, the left eye was erythematous and edematous starting at the left medial canthus, tracking across the upper lid to the lateral angle of the eye, and extending inferiorly to involve the medial portion of the lower lid. A pinpoint sinus tract was visible on the medial aspect of the upper eyelid and was actively draining serosanguinous fluid. Head computed tomography demonstrated findings consistent with left preseptal orbital cellulitis and a small developing phlegmon. Patient was started on intravenous broad-spectrum antibiotics but failed to improve after 3 days. Incision and drainage were performed, which revealed a live 1-cm larva.
Fifth (erythema infectiosum) and sixth (roseola infantum) diseases are common rash illnesses of c... more Fifth (erythema infectiosum) and sixth (roseola infantum) diseases are common rash illnesses of childhood that have long been recognized in clinical medicine. The discovery of the viruses that cause these illnesses has revealed relationships with other syndromes. Primary infection with the agent of erythema infectiosum, human parvovirus B19, is associated with transient aplastic crisis in hemolytic anemia, arthropathy in adults, chronic anemia in immunocompromised patients, and nonimmune fetal hydrops in pregnant women. The only documented illness associated with primary infection with human herpesvirus 6 is roseola or exanthema subitum in young children. However, reactivated infections in adults and immunocompromised patients may be associated with serious illness such as encephalitis/encephalopathy, and bone marrow suppression leading to transplant failure or graft-versus-host disease. Diagnostic studies for both viruses have been limited, although reliable serologic tests for human parvovirus B19 have recently become available. Diagnosis of human herpesvirus 6 remains problematic, because current tests cannot differentiate primary from reactivated disease. This is more of an issue for the putative relationship of these viruses to more chronic conditions, such as rheumatologic disease for human parvovirus B19 and multiple sclerosis for human herpesvirus 6. The relationship between the viruses and these conditions remains controversial, and better diagnostic tests and further information on viral pathogenesis for both viruses are required in order to make a reliable judgment in this regard.
To establish a renewable source of parvovirus B19 antigens for diagnostic tests, gene sequences f... more To establish a renewable source of parvovirus B19 antigens for diagnostic tests, gene sequences for the viral capsid proteins, VP1 and VP2, were cloned into baculovirus expression vectors and the recombinant viruses used to infect Sf9 insect cells. Cell lysates examined by immunoblotting demonstrated reactive proteins corresponding to the expected sizes of native VP1 (83 kDa) and VP2 (58 kDa). The VP2 protein was produced efficiently in quantity and self-assembled into empty capsids as shown by density equilibration in a CsCl step gradient. The VP2 protein was purified and used as an antigen in antibody-capture enzyme immunoassays for the detection of B19 IgG and IgM antibodies. Compared to a standard antibody-capture EIA based on whole viral antigen, the VP2-EIA gave a sensitivity of 100% and specificity of 97% in detection of B19 IgM in 138 patients suspected of B19 infection. No IgM-positive specimens were missed. IgG detection yielded a sensitivity of 100% and specificity of 96% in the same population. Recombinant VP2 capsid proteins expressed in baculovirus-infected insect cells can substitute for serum-derived B19 virus in standard antibody-capture EIA for the detection of B19 IgG and IgM with comparable results.
Human parvovirus B19 (B19) crosses the placenta causing fetal death. We used an indirect capture ... more Human parvovirus B19 (B19) crosses the placenta causing fetal death. We used an indirect capture enzyme immunoassay to measure IgG to B19 in sera of 845 subjects from 2 groups. The first group included 405 women (mean age, 30 years) composed of 85 pediatric nurses and 130 other female hospital employees, 122 women employed caring for preschool children and 68 mothers of preschool children enrolled in day care. Twenty-eight percent of all these women were seropositive. Seropositivity was unrelated to occupational group. Four of 235 women observed between 1983 and 1987 for a mean of 435 days/woman acquired B19 infections (an annual seroconversion rate of 1.5%). We investigated intrafamilial associations of B19 infection in a second group of 440 subjects from 111 families. Seropositivity of parents was not associated with seropositivity of their children. Seropositivity of one spouse was not associated with seropositivity of the cospouse. However, of 47 seropositive older siblings, 32 (68%) of their younger siblings were seropositive, compared to 20 (18%) seropositive younger siblings of 112 seronegative older siblings (P less than 0.001). B19 infections increased with age from 19% for those younger than 10 years to 67% for those older than 49 years. For all ages females had a higher rate (51%) of B19 infection than males (38%). These data suggest that children may be more susceptible to B19 than adults and B19 infections occur infrequently among women younger than 40 years of age. However, during local outbreaks the B19 infection rate for susceptible pregnant women remains unknown.
Pharmacopeial Forum 33(3) [May-June 2007] included a Stimuli article titled "Proposed Change to A... more Pharmacopeial Forum 33(3) [May-June 2007] included a Stimuli article titled "Proposed Change to Acceptance Criteria for Dissolution Performance Verification Testing." This Stimuli article proposed changing the form of the acceptance criteria for the Performance Verification Test (PVT) associated with USP Dissolution <711> to make the PVT consistent with the International Organization for Standardization's recommendations for proficiency testing. The article elicited five comments, which are abstracted here with USP responses.
Clinical and diagnostic laboratory immunology, 1996
Five hundred thirty-three liver transplant recipients were seen for follow-up care over a 6-month... more Five hundred thirty-three liver transplant recipients were seen for follow-up care over a 6-month period. Of these, 23 (4.3%) had a hemoglobin level of < or = 9 g/dl, with 19 being eligible for inclusion in this study. The median hemoglobin level was 8.7 g/dl. Two patients had iron-deficiency anemia. All of the patients were on therapeutic drugs which can suppress erythropoiesis or shorten the lifespan of mature erythrocytes. Six patients (31.6%) were viremic for human parvovirus B19 but none was B19 immunoglobulin M seropositive. Two patients were immunoglobulin M seropositive for cytomegalovirus. The patients with circulating B19 DNA were not easily distinguished from those without the virus by their laboratory results. The absence of reticulocyte counts for these patients contributed to this inability to differentiate B19 from other causes of anemia, particularly drug myelotoxicity. The high likelihood of making a specific diagnosis with the increasing availability of PCR shou...
Research in mental health has generally used evaluation and outcome measures different from those... more Research in mental health has generally used evaluation and outcome measures different from those applied in other medical specialties. We evaluated the utility of a general health measure, the Quality of Well-Being (QWB) scale, in older patients with psychosis. The QWB and standardized rating scales for assessing psychopathology, cognitive impairment, physical comorbidity, and neuroleptic-induced tardive dyskinesia were administered to 85 patients with functional psychoses (mostly schizophrenia or schizoaffective disorder) and 39 normal comparison subjects over age 45. The patients were more impaired than normal comparison subjects on the QWB and other rating scales. The QWB score was affected more by severity of positive symptoms than by any non-psychopathology-related variables. The patients&amp;amp;#39; QWB scores were similar to those of previously studied ambulatory patients with AIDS. Use of the QWB scale may allow direct comparisons of the impact of different psychiatric and physical disorders on the quality of life.
Blood donor units are not screened for human parvovirus B19 (B19) even though it can be acquired ... more Blood donor units are not screened for human parvovirus B19 (B19) even though it can be acquired via blood products. We estimated the prevalence of B19 in a US volunteer blood donor population and determined the clinical outcomes of transfusion recipients. Donor units were screened for B19 DNA by PCR, and positive units analyzed by EIA for B19 Ig. Unit usage was determined and recipient chart review conducted. B19 DNA was detected in 11/9, 568 allogeneic units (0.1%), of which 3 had no measurable B19 Ig. One individual developed anemia consistent with B19 infection after receiving a DNA+ unit lacking B19 Ig. The apparent low incidence of disease in patients transfused with B19 DNA+ components may be due to coexistence of neutralizing antibodies in donors and/or recipients.
The long-term consequences of parvovirus 61 9 infection in transfusion recipients are not known, ... more The long-term consequences of parvovirus 61 9 infection in transfusion recipients are not known, and thus the value of 619 screening of blood donors remains unresolved. Hemophiliacs, at risk for 61 9 through their chronic exposure to clotting factor concentrates, have frequent, close medical follow-up and thereby constitute an ideal group in which to study the hematologic sequelae of 61 9 infection. Study Design and Methods: An enzyme-linked immunosorbent assay was used to detect 619 IgG and IgM and the polymerase chain reaction was used to detect 61 9 DNA in frozen, stored plasma samples, obtained between 1987 and 1994, from 136 subjects with hemophilia, including 71 who were human immunodeficiency virus (HIV)-positive and 65 who were HIV-negative. Then the results of the tests were compared with clinical hematologic data and blood product usage data. Results: 619 seroprevalence in the hemophilic cohort was 81.6 percent (111/136), including 74.6 percent (53/71) of HIV-positive and 89.2 percent (58/65) of HIV-negative hemophiliacs. It was not affected by age, type or severity of hemophilia, HIV status, CD4 number, or yearly blood product usage. Only 1 (0.7%) of the 136 samples was positive for 619 IgM and none was positive in polymerase chain reaction for 619 DNA. After adjusting for HIV status, there were no differences between 619positive and 61 9-negative hemophiliacs in hematologic values, CD4 counts, or blood product use. Conclusion: Although 61 9 IgG seroprevalence in this hemophilic cohort is high and indicative of past B19 infection, there is no detectable 61 9 viral activity or any associated long-term clinical or hematologic sequelae.
Although infection with parvovirus B19 (B19) during pregnancy may cause fetal demise, the true in... more Although infection with parvovirus B19 (B19) during pregnancy may cause fetal demise, the true incidence of intrauterine infection is unknown. For 19 women with serologically confirmed B19 infections between 4 and 38 weeks of gestation, we performed follow-up examinations of their infants. Serial sonograms of the 19 fetuses showed that none developed hydrops. All 19 women delivered healthy term infants. Cord sera of four infants were tested for IgM to B19 and three were positive. Between 3 and 21 months of age, all 19 infants had normal physical examinations, developmental evaluations and hematocrits; and 16 lacked IgG to B19. One infant who was IgM-positive to B19 at birth was IgM-positive at age 7 months when he also had an IgG titer to B19 of 1:500,000 (mother&#39;s concurrent titer, 1:10,000), and had B19 DNA in serum detected by polymerase chain reaction. The other two infants who were IgM-positive at birth were IgM- and IgG-negative by 11 and 16 months of age. These results suggest that intrauterine B19 infection may be frequent and occasionally cause an asymptomatic postnatal infection.
To define the intrauterine viral transmission rate during primary maternal parvovirus B19 infecti... more To define the intrauterine viral transmission rate during primary maternal parvovirus B19 infection and identify factors that may influence this rate. Forty-three pregnant women at two medical centers were identified with a primary B19 infection and followed to delivery. At delivery maternal and infant (umbilical cord) blood was obtained for B19 serologic and virologic PCR testing. All of the women delivered healthy infants at term and none was hydropic. Overall 22 (51%) of the 43 infants had some evidence of a congenital B19 infection. B19-specific IgM was detected in 11 infants at delivery, B19 IgA was detected in 10 and B19 DNA was detectable by PCR in 11 infants. One infant was negative at birth but became positive for IgM, IgA and PCR at 6 weeks of age. No association was found between the likelihood of intrauterine infection and: maternal age; symptomatic maternal infection; method of delivery; maternal IgG titer at delivery; maternal IgG avidity at delivery; or maternal viremia at delivery. Intrauterine infection was associated with maternal IgM positivity at delivery; this association may have been a result of maternal infection occurring later in gestation. Although the incidence of intrauterine hydrops and fetal demise after maternal infection is low, there is a high rate of intrauterine viral infection that occurs throughout gestation and yields newborns who, although infected in utero, are asymptomatic at birth.
Cytomegalovirus (CMV) infection is very common throughout the world, and has become more of a ped... more Cytomegalovirus (CMV) infection is very common throughout the world, and has become more of a pediatric clinical concern given the high incidence of congenital CMV infections as well as the increasing numbers of immunocompromised patients. Because of this, the need for antiviral therapies in infants and neonates is growing. Currently, there are four antivirals available that are active against CMV: ganciclovir, valganciclovir, foscarnet, and cidofovir. At this time, none have approved indications for use in children. Although there are limited data regarding the dose, pharmacokinetics (PK), safety, and adverse events for some of these antivirals, ganciclovir, and its oral prodrug valganciclovir, have been the best studied in the infant and neonate populations. In general, pharmaceutical PK studies in young children are limited by the constraints of sampling difficulties and blood volume requirements; fewer sampling times and studies may be available for drug evaluation. Given this caveat, ganciclovir and valganciclovir PK in children thus far appears to follow a monocompartmental model, contrary to what has been described in adults. However, when normalized for weight, the volume of distribution, clearance, and half-life of ganciclovir are similar to those found in adults. Given the findings that ganciclovir (and thus valganciclovir) clearance is directly proportionate to renal function, care must be taken when administering the drug to patients with impaired renal function. Recent studies evaluating valganciclovir PK in infants (at a dose of 16 mg/kg every 12 hours) have shown similar areas under the plasma concentration-time curve (AUCs) to intravenous ganciclovir (at a dose of 6 mg/kg every 12 hours), and that these AUCs remain quite stable over a number of weeks. As seen in adults, oral ganciclovir has a low bioavailability (4.8% in a pediatric analysis) and is therefore a poor alternative for treating serious CMV infections. Neutropenia is the most frequent toxicity associated with ganciclovir and valganciclovir therapy, whereas significant (and possibly irreversible) renal toxicity can be seen with cidofovir. Foscarnet administration can also result in renal toxicity as well as significant electrolyte imbalances. Several of these drugs have potential toxicities that are of concern, including carcinogenesis, teratogenesis, and azospermia (ganciclovir, valganciclovir, and cidofovir) and deposition into bone or dentition (foscarnet) that may have significant implications when treating an infant. Given these potential ill effects, careful consideration of the indications for the clinical use of these antivirals is necessary before using them for CMV infection in neonates and infants.
To assess the risk of maternal parvovirus B19 infection from exposure to various sources and the ... more To assess the risk of maternal parvovirus B19 infection from exposure to various sources and the fetal morbidity of those infections. We obtained demographic and occupational information about pregnant women exposed to sources of B19 and about the nature and duration of the exposures. We performed serologic testing 10-14 days after exposure using an indirect capture enzyme-linked immunosorbent assay. Women with immunoglobulin (Ig) M were examined with weekly ultrasound until 12 weeks after exposure, and the outcome of the pregnancy was ascertained from interviews with patients and their obstetricians. Logistic regression analysis was used to determine risk factors for maternal immunity and infection by B19. Of 618 pregnant women exposed, 307 (49.7%) were immune to B19, 259 remained susceptible after exposure, and 52 (16.7% of all susceptibles) contracted B19 infection. None of the 52 fetuses of infected women developed nonimmune hydrops, and there were no fetal deaths attributable to B19 in this group. The relative risk of maternal B19 infection was 2.8 if the source was a related child living in the household (95% confidence interval 1.7, 4.6; P &lt; .001). No significant differences were found for maternal B19 infection in eight categories of maternal occupation. Maternal symptoms of polyarthralgia (46%), fever (19%), and nonspecific rash (38%) were significantly more common (P &lt; .001) in IgM-positive patients than in noninfected women (4.1%, 2.8%, and 5.7%, respectively). Only 17 (33%) of the IgM-positive women were entirely asymptomatic. The risk of maternal B19 infection in pregnancy could not be predicted by a gravida&#39;s occupation, but it was significantly higher when the source of exposure was her own child. The fetal risk of nonimmune hydrops after maternal B19 infection must be very low. As a consequence, exclusion of pregnant women from the workplace during endemic periods with seasonal clusters of cases is not justified. Weekly fetal ultrasound evaluation in these cases carries a low yield.
Babesiosis is a parasitic infection of the red blood cells most often acquired by a tick bite. As... more Babesiosis is a parasitic infection of the red blood cells most often acquired by a tick bite. As it has also been known to be transmitted vertically and via transfusion, neonates have occasionally been reported with the infection. Here, we report a series of three premature neonates who acquired babesiosis via blood transfusion from a single donor, one of whom had difficulty clearing the infection and required multiple antimicrobials.
We diagnosed infections from human parvovirus B19 in three patients by using dot-blot hybridizati... more We diagnosed infections from human parvovirus B19 in three patients by using dot-blot hybridization and a polymerase chain reaction to detect B19 DNA and using an enzyme immunoassay to detect IgG and IgM to B19. For 5 months a 5-year-old boy with acute lymphoblastic leukemia in remission had anemia without reticulocytes or bone marrow erythrocyte precursors. His serum lacked IgG and IgM to B19 but contained B19 DNA. He received gamma globulin intravenously (0.4 gm/kg/day for 5 days); his viremia promptly cleared and reticulocytosis developed. A 14-year-old boy with acute lymphoblastic leukemia in remission had fever, rash, neutropenia (less than 300 leukocytes/mm3), and a hemophagocytic syndrome lasting 3 weeks. His serum contained IgM to B19 and B19 DNA. Without therapy, IgG to B19 developed; although low levels of B19 DNA persisted, the leukocyte count returned to normal. In a 19-year-old patient with systemic lupus erythematosus and hemolytic anemia, an aplastic crisis lasted 2 weeks. Her serum lacked IgG and IgM to B19 but contained B19 DNA. Without therapy, IgG and IgM to B19 appeared, viremia diminished, and reticulocytosis occurred. These patients illustrate the varied manifestations of chronic B19 infections, the importance of DNA detection for diagnosis, and the possible efficacy of gamma globulin therapy.
Because human parvovirus B19 (B19) infections are common in children, and maternal infection of p... more Because human parvovirus B19 (B19) infections are common in children, and maternal infection of pregnant women may cause fetal death, risk factors for B19 infections for hospital and school employees were identified during an endemic period. By serologic testing, 2730 employees of 135 schools in three school systems and 751 employees of a hospital were monitored. Of these, 60% were initially seropositive. After adjusting for age, race, and gender, risk factors for seropositivity were contact with children 5-18 years old at home (odds ratio [OR] = 1.2), at work (OR = 1.2), and employment in elementary schools in school system 2 (OR = 1.4). Over 42 months, 1 of 198 susceptible hospital employees seroconverted versus 62 of 927 school employees. Four factors associated with seroconversion were employment at elementary schools in system 2, contact with children 5-11 years old at home or with children 5-18 years old at work, and age &lt; 30 years. Those in daily contact with school-age children had a fivefold increased annual occupational risk for B19 infection.
Recent studies have suggested that providing free sample packs of baby items to newly delivered p... more Recent studies have suggested that providing free sample packs of baby items to newly delivered parents may adversely influence parental health behavior. To determine the extent of this practice in Virginia, the head nurses of all 68 newborn nurseries and a random sample of 200 pediatricians were surveyed. Formula samples were being distributed at all hospitals. Formula packs were given to breast-feeding mothers at 65 (95%) hospitals although only 66 percent of the surveyed pediatricians approved of this practice. Samples of baby items other than formula (e.g., baby powder) were being distributed at 66 (97%) hospitals. Some physicians (18%) objected to the distribution of these nonformula samples, and others were not familiar with the content of these packs. In most instances, the hospital medical staff had not voted to approve the distribution of these packs. Parents were being informed only rarely about the source and intent of the packs. The provision of sample packs to newly delivered parents affects approximately 3,000,000 babies each year in the United States. The short- and long-term effects of providing these packs have been inadequately explored. Physicians should make an active decision whether to distribute sample packs. Those physicians choosing to dispense these samples may wish to review and edit the content of the packs and to enclose in the pack a brief note explaining that the provision of the products does not constitute a medical endorsement.
A 13-month-old Caucasian female presented with erythema, swelling, and pain of the left periorbit... more A 13-month-old Caucasian female presented with erythema, swelling, and pain of the left periorbital region. On admission, her vital signs were normal, and complete blood count did not reveal abnormalities. Blood and eye cultures were collected. On physical examination, the left eye was erythematous and edematous starting at the left medial canthus, tracking across the upper lid to the lateral angle of the eye, and extending inferiorly to involve the medial portion of the lower lid. A pinpoint sinus tract was visible on the medial aspect of the upper eyelid and was actively draining serosanguinous fluid. Head computed tomography demonstrated findings consistent with left preseptal orbital cellulitis and a small developing phlegmon. Patient was started on intravenous broad-spectrum antibiotics but failed to improve after 3 days. Incision and drainage were performed, which revealed a live 1-cm larva.
Fifth (erythema infectiosum) and sixth (roseola infantum) diseases are common rash illnesses of c... more Fifth (erythema infectiosum) and sixth (roseola infantum) diseases are common rash illnesses of childhood that have long been recognized in clinical medicine. The discovery of the viruses that cause these illnesses has revealed relationships with other syndromes. Primary infection with the agent of erythema infectiosum, human parvovirus B19, is associated with transient aplastic crisis in hemolytic anemia, arthropathy in adults, chronic anemia in immunocompromised patients, and nonimmune fetal hydrops in pregnant women. The only documented illness associated with primary infection with human herpesvirus 6 is roseola or exanthema subitum in young children. However, reactivated infections in adults and immunocompromised patients may be associated with serious illness such as encephalitis/encephalopathy, and bone marrow suppression leading to transplant failure or graft-versus-host disease. Diagnostic studies for both viruses have been limited, although reliable serologic tests for human parvovirus B19 have recently become available. Diagnosis of human herpesvirus 6 remains problematic, because current tests cannot differentiate primary from reactivated disease. This is more of an issue for the putative relationship of these viruses to more chronic conditions, such as rheumatologic disease for human parvovirus B19 and multiple sclerosis for human herpesvirus 6. The relationship between the viruses and these conditions remains controversial, and better diagnostic tests and further information on viral pathogenesis for both viruses are required in order to make a reliable judgment in this regard.
To establish a renewable source of parvovirus B19 antigens for diagnostic tests, gene sequences f... more To establish a renewable source of parvovirus B19 antigens for diagnostic tests, gene sequences for the viral capsid proteins, VP1 and VP2, were cloned into baculovirus expression vectors and the recombinant viruses used to infect Sf9 insect cells. Cell lysates examined by immunoblotting demonstrated reactive proteins corresponding to the expected sizes of native VP1 (83 kDa) and VP2 (58 kDa). The VP2 protein was produced efficiently in quantity and self-assembled into empty capsids as shown by density equilibration in a CsCl step gradient. The VP2 protein was purified and used as an antigen in antibody-capture enzyme immunoassays for the detection of B19 IgG and IgM antibodies. Compared to a standard antibody-capture EIA based on whole viral antigen, the VP2-EIA gave a sensitivity of 100% and specificity of 97% in detection of B19 IgM in 138 patients suspected of B19 infection. No IgM-positive specimens were missed. IgG detection yielded a sensitivity of 100% and specificity of 96% in the same population. Recombinant VP2 capsid proteins expressed in baculovirus-infected insect cells can substitute for serum-derived B19 virus in standard antibody-capture EIA for the detection of B19 IgG and IgM with comparable results.
Human parvovirus B19 (B19) crosses the placenta causing fetal death. We used an indirect capture ... more Human parvovirus B19 (B19) crosses the placenta causing fetal death. We used an indirect capture enzyme immunoassay to measure IgG to B19 in sera of 845 subjects from 2 groups. The first group included 405 women (mean age, 30 years) composed of 85 pediatric nurses and 130 other female hospital employees, 122 women employed caring for preschool children and 68 mothers of preschool children enrolled in day care. Twenty-eight percent of all these women were seropositive. Seropositivity was unrelated to occupational group. Four of 235 women observed between 1983 and 1987 for a mean of 435 days/woman acquired B19 infections (an annual seroconversion rate of 1.5%). We investigated intrafamilial associations of B19 infection in a second group of 440 subjects from 111 families. Seropositivity of parents was not associated with seropositivity of their children. Seropositivity of one spouse was not associated with seropositivity of the cospouse. However, of 47 seropositive older siblings, 32 (68%) of their younger siblings were seropositive, compared to 20 (18%) seropositive younger siblings of 112 seronegative older siblings (P less than 0.001). B19 infections increased with age from 19% for those younger than 10 years to 67% for those older than 49 years. For all ages females had a higher rate (51%) of B19 infection than males (38%). These data suggest that children may be more susceptible to B19 than adults and B19 infections occur infrequently among women younger than 40 years of age. However, during local outbreaks the B19 infection rate for susceptible pregnant women remains unknown.
Pharmacopeial Forum 33(3) [May-June 2007] included a Stimuli article titled "Proposed Change to A... more Pharmacopeial Forum 33(3) [May-June 2007] included a Stimuli article titled "Proposed Change to Acceptance Criteria for Dissolution Performance Verification Testing." This Stimuli article proposed changing the form of the acceptance criteria for the Performance Verification Test (PVT) associated with USP Dissolution <711> to make the PVT consistent with the International Organization for Standardization's recommendations for proficiency testing. The article elicited five comments, which are abstracted here with USP responses.
Clinical and diagnostic laboratory immunology, 1996
Five hundred thirty-three liver transplant recipients were seen for follow-up care over a 6-month... more Five hundred thirty-three liver transplant recipients were seen for follow-up care over a 6-month period. Of these, 23 (4.3%) had a hemoglobin level of < or = 9 g/dl, with 19 being eligible for inclusion in this study. The median hemoglobin level was 8.7 g/dl. Two patients had iron-deficiency anemia. All of the patients were on therapeutic drugs which can suppress erythropoiesis or shorten the lifespan of mature erythrocytes. Six patients (31.6%) were viremic for human parvovirus B19 but none was B19 immunoglobulin M seropositive. Two patients were immunoglobulin M seropositive for cytomegalovirus. The patients with circulating B19 DNA were not easily distinguished from those without the virus by their laboratory results. The absence of reticulocyte counts for these patients contributed to this inability to differentiate B19 from other causes of anemia, particularly drug myelotoxicity. The high likelihood of making a specific diagnosis with the increasing availability of PCR shou...
Research in mental health has generally used evaluation and outcome measures different from those... more Research in mental health has generally used evaluation and outcome measures different from those applied in other medical specialties. We evaluated the utility of a general health measure, the Quality of Well-Being (QWB) scale, in older patients with psychosis. The QWB and standardized rating scales for assessing psychopathology, cognitive impairment, physical comorbidity, and neuroleptic-induced tardive dyskinesia were administered to 85 patients with functional psychoses (mostly schizophrenia or schizoaffective disorder) and 39 normal comparison subjects over age 45. The patients were more impaired than normal comparison subjects on the QWB and other rating scales. The QWB score was affected more by severity of positive symptoms than by any non-psychopathology-related variables. The patients&amp;amp;#39; QWB scores were similar to those of previously studied ambulatory patients with AIDS. Use of the QWB scale may allow direct comparisons of the impact of different psychiatric and physical disorders on the quality of life.
Blood donor units are not screened for human parvovirus B19 (B19) even though it can be acquired ... more Blood donor units are not screened for human parvovirus B19 (B19) even though it can be acquired via blood products. We estimated the prevalence of B19 in a US volunteer blood donor population and determined the clinical outcomes of transfusion recipients. Donor units were screened for B19 DNA by PCR, and positive units analyzed by EIA for B19 Ig. Unit usage was determined and recipient chart review conducted. B19 DNA was detected in 11/9, 568 allogeneic units (0.1%), of which 3 had no measurable B19 Ig. One individual developed anemia consistent with B19 infection after receiving a DNA+ unit lacking B19 Ig. The apparent low incidence of disease in patients transfused with B19 DNA+ components may be due to coexistence of neutralizing antibodies in donors and/or recipients.
The long-term consequences of parvovirus 61 9 infection in transfusion recipients are not known, ... more The long-term consequences of parvovirus 61 9 infection in transfusion recipients are not known, and thus the value of 619 screening of blood donors remains unresolved. Hemophiliacs, at risk for 61 9 through their chronic exposure to clotting factor concentrates, have frequent, close medical follow-up and thereby constitute an ideal group in which to study the hematologic sequelae of 61 9 infection. Study Design and Methods: An enzyme-linked immunosorbent assay was used to detect 619 IgG and IgM and the polymerase chain reaction was used to detect 61 9 DNA in frozen, stored plasma samples, obtained between 1987 and 1994, from 136 subjects with hemophilia, including 71 who were human immunodeficiency virus (HIV)-positive and 65 who were HIV-negative. Then the results of the tests were compared with clinical hematologic data and blood product usage data. Results: 619 seroprevalence in the hemophilic cohort was 81.6 percent (111/136), including 74.6 percent (53/71) of HIV-positive and 89.2 percent (58/65) of HIV-negative hemophiliacs. It was not affected by age, type or severity of hemophilia, HIV status, CD4 number, or yearly blood product usage. Only 1 (0.7%) of the 136 samples was positive for 619 IgM and none was positive in polymerase chain reaction for 619 DNA. After adjusting for HIV status, there were no differences between 619positive and 61 9-negative hemophiliacs in hematologic values, CD4 counts, or blood product use. Conclusion: Although 61 9 IgG seroprevalence in this hemophilic cohort is high and indicative of past B19 infection, there is no detectable 61 9 viral activity or any associated long-term clinical or hematologic sequelae.
Although infection with parvovirus B19 (B19) during pregnancy may cause fetal demise, the true in... more Although infection with parvovirus B19 (B19) during pregnancy may cause fetal demise, the true incidence of intrauterine infection is unknown. For 19 women with serologically confirmed B19 infections between 4 and 38 weeks of gestation, we performed follow-up examinations of their infants. Serial sonograms of the 19 fetuses showed that none developed hydrops. All 19 women delivered healthy term infants. Cord sera of four infants were tested for IgM to B19 and three were positive. Between 3 and 21 months of age, all 19 infants had normal physical examinations, developmental evaluations and hematocrits; and 16 lacked IgG to B19. One infant who was IgM-positive to B19 at birth was IgM-positive at age 7 months when he also had an IgG titer to B19 of 1:500,000 (mother&#39;s concurrent titer, 1:10,000), and had B19 DNA in serum detected by polymerase chain reaction. The other two infants who were IgM-positive at birth were IgM- and IgG-negative by 11 and 16 months of age. These results suggest that intrauterine B19 infection may be frequent and occasionally cause an asymptomatic postnatal infection.
To define the intrauterine viral transmission rate during primary maternal parvovirus B19 infecti... more To define the intrauterine viral transmission rate during primary maternal parvovirus B19 infection and identify factors that may influence this rate. Forty-three pregnant women at two medical centers were identified with a primary B19 infection and followed to delivery. At delivery maternal and infant (umbilical cord) blood was obtained for B19 serologic and virologic PCR testing. All of the women delivered healthy infants at term and none was hydropic. Overall 22 (51%) of the 43 infants had some evidence of a congenital B19 infection. B19-specific IgM was detected in 11 infants at delivery, B19 IgA was detected in 10 and B19 DNA was detectable by PCR in 11 infants. One infant was negative at birth but became positive for IgM, IgA and PCR at 6 weeks of age. No association was found between the likelihood of intrauterine infection and: maternal age; symptomatic maternal infection; method of delivery; maternal IgG titer at delivery; maternal IgG avidity at delivery; or maternal viremia at delivery. Intrauterine infection was associated with maternal IgM positivity at delivery; this association may have been a result of maternal infection occurring later in gestation. Although the incidence of intrauterine hydrops and fetal demise after maternal infection is low, there is a high rate of intrauterine viral infection that occurs throughout gestation and yields newborns who, although infected in utero, are asymptomatic at birth.
Cytomegalovirus (CMV) infection is very common throughout the world, and has become more of a ped... more Cytomegalovirus (CMV) infection is very common throughout the world, and has become more of a pediatric clinical concern given the high incidence of congenital CMV infections as well as the increasing numbers of immunocompromised patients. Because of this, the need for antiviral therapies in infants and neonates is growing. Currently, there are four antivirals available that are active against CMV: ganciclovir, valganciclovir, foscarnet, and cidofovir. At this time, none have approved indications for use in children. Although there are limited data regarding the dose, pharmacokinetics (PK), safety, and adverse events for some of these antivirals, ganciclovir, and its oral prodrug valganciclovir, have been the best studied in the infant and neonate populations. In general, pharmaceutical PK studies in young children are limited by the constraints of sampling difficulties and blood volume requirements; fewer sampling times and studies may be available for drug evaluation. Given this caveat, ganciclovir and valganciclovir PK in children thus far appears to follow a monocompartmental model, contrary to what has been described in adults. However, when normalized for weight, the volume of distribution, clearance, and half-life of ganciclovir are similar to those found in adults. Given the findings that ganciclovir (and thus valganciclovir) clearance is directly proportionate to renal function, care must be taken when administering the drug to patients with impaired renal function. Recent studies evaluating valganciclovir PK in infants (at a dose of 16 mg/kg every 12 hours) have shown similar areas under the plasma concentration-time curve (AUCs) to intravenous ganciclovir (at a dose of 6 mg/kg every 12 hours), and that these AUCs remain quite stable over a number of weeks. As seen in adults, oral ganciclovir has a low bioavailability (4.8% in a pediatric analysis) and is therefore a poor alternative for treating serious CMV infections. Neutropenia is the most frequent toxicity associated with ganciclovir and valganciclovir therapy, whereas significant (and possibly irreversible) renal toxicity can be seen with cidofovir. Foscarnet administration can also result in renal toxicity as well as significant electrolyte imbalances. Several of these drugs have potential toxicities that are of concern, including carcinogenesis, teratogenesis, and azospermia (ganciclovir, valganciclovir, and cidofovir) and deposition into bone or dentition (foscarnet) that may have significant implications when treating an infant. Given these potential ill effects, careful consideration of the indications for the clinical use of these antivirals is necessary before using them for CMV infection in neonates and infants.
To assess the risk of maternal parvovirus B19 infection from exposure to various sources and the ... more To assess the risk of maternal parvovirus B19 infection from exposure to various sources and the fetal morbidity of those infections. We obtained demographic and occupational information about pregnant women exposed to sources of B19 and about the nature and duration of the exposures. We performed serologic testing 10-14 days after exposure using an indirect capture enzyme-linked immunosorbent assay. Women with immunoglobulin (Ig) M were examined with weekly ultrasound until 12 weeks after exposure, and the outcome of the pregnancy was ascertained from interviews with patients and their obstetricians. Logistic regression analysis was used to determine risk factors for maternal immunity and infection by B19. Of 618 pregnant women exposed, 307 (49.7%) were immune to B19, 259 remained susceptible after exposure, and 52 (16.7% of all susceptibles) contracted B19 infection. None of the 52 fetuses of infected women developed nonimmune hydrops, and there were no fetal deaths attributable to B19 in this group. The relative risk of maternal B19 infection was 2.8 if the source was a related child living in the household (95% confidence interval 1.7, 4.6; P &lt; .001). No significant differences were found for maternal B19 infection in eight categories of maternal occupation. Maternal symptoms of polyarthralgia (46%), fever (19%), and nonspecific rash (38%) were significantly more common (P &lt; .001) in IgM-positive patients than in noninfected women (4.1%, 2.8%, and 5.7%, respectively). Only 17 (33%) of the IgM-positive women were entirely asymptomatic. The risk of maternal B19 infection in pregnancy could not be predicted by a gravida&#39;s occupation, but it was significantly higher when the source of exposure was her own child. The fetal risk of nonimmune hydrops after maternal B19 infection must be very low. As a consequence, exclusion of pregnant women from the workplace during endemic periods with seasonal clusters of cases is not justified. Weekly fetal ultrasound evaluation in these cases carries a low yield.
Babesiosis is a parasitic infection of the red blood cells most often acquired by a tick bite. As... more Babesiosis is a parasitic infection of the red blood cells most often acquired by a tick bite. As it has also been known to be transmitted vertically and via transfusion, neonates have occasionally been reported with the infection. Here, we report a series of three premature neonates who acquired babesiosis via blood transfusion from a single donor, one of whom had difficulty clearing the infection and required multiple antimicrobials.
We diagnosed infections from human parvovirus B19 in three patients by using dot-blot hybridizati... more We diagnosed infections from human parvovirus B19 in three patients by using dot-blot hybridization and a polymerase chain reaction to detect B19 DNA and using an enzyme immunoassay to detect IgG and IgM to B19. For 5 months a 5-year-old boy with acute lymphoblastic leukemia in remission had anemia without reticulocytes or bone marrow erythrocyte precursors. His serum lacked IgG and IgM to B19 but contained B19 DNA. He received gamma globulin intravenously (0.4 gm/kg/day for 5 days); his viremia promptly cleared and reticulocytosis developed. A 14-year-old boy with acute lymphoblastic leukemia in remission had fever, rash, neutropenia (less than 300 leukocytes/mm3), and a hemophagocytic syndrome lasting 3 weeks. His serum contained IgM to B19 and B19 DNA. Without therapy, IgG to B19 developed; although low levels of B19 DNA persisted, the leukocyte count returned to normal. In a 19-year-old patient with systemic lupus erythematosus and hemolytic anemia, an aplastic crisis lasted 2 weeks. Her serum lacked IgG and IgM to B19 but contained B19 DNA. Without therapy, IgG and IgM to B19 appeared, viremia diminished, and reticulocytosis occurred. These patients illustrate the varied manifestations of chronic B19 infections, the importance of DNA detection for diagnosis, and the possible efficacy of gamma globulin therapy.
Because human parvovirus B19 (B19) infections are common in children, and maternal infection of p... more Because human parvovirus B19 (B19) infections are common in children, and maternal infection of pregnant women may cause fetal death, risk factors for B19 infections for hospital and school employees were identified during an endemic period. By serologic testing, 2730 employees of 135 schools in three school systems and 751 employees of a hospital were monitored. Of these, 60% were initially seropositive. After adjusting for age, race, and gender, risk factors for seropositivity were contact with children 5-18 years old at home (odds ratio [OR] = 1.2), at work (OR = 1.2), and employment in elementary schools in school system 2 (OR = 1.4). Over 42 months, 1 of 198 susceptible hospital employees seroconverted versus 62 of 927 school employees. Four factors associated with seroconversion were employment at elementary schools in system 2, contact with children 5-11 years old at home or with children 5-18 years old at work, and age &lt; 30 years. Those in daily contact with school-age children had a fivefold increased annual occupational risk for B19 infection.
Recent studies have suggested that providing free sample packs of baby items to newly delivered p... more Recent studies have suggested that providing free sample packs of baby items to newly delivered parents may adversely influence parental health behavior. To determine the extent of this practice in Virginia, the head nurses of all 68 newborn nurseries and a random sample of 200 pediatricians were surveyed. Formula samples were being distributed at all hospitals. Formula packs were given to breast-feeding mothers at 65 (95%) hospitals although only 66 percent of the surveyed pediatricians approved of this practice. Samples of baby items other than formula (e.g., baby powder) were being distributed at 66 (97%) hospitals. Some physicians (18%) objected to the distribution of these nonformula samples, and others were not familiar with the content of these packs. In most instances, the hospital medical staff had not voted to approve the distribution of these packs. Parents were being informed only rarely about the source and intent of the packs. The provision of sample packs to newly delivered parents affects approximately 3,000,000 babies each year in the United States. The short- and long-term effects of providing these packs have been inadequately explored. Physicians should make an active decision whether to distribute sample packs. Those physicians choosing to dispense these samples may wish to review and edit the content of the packs and to enclose in the pack a brief note explaining that the provision of the products does not constitute a medical endorsement.
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Papers by William Koch