1040 Prophylactic infusions with an unmodified intravenous immunoglobulin product causing few side-effects in patients with antibody deficiency syndromes

Summary Thirty-two patients with common variable immunodeficiency (CVID) and two patients with IgA and IgG subclass deficiency received a total of 1,040 intravenous (i.v.) infusions during 60 patient years with 7,575 g of a new immunoglobulin (Ig) preparation. The content of prekallikrein activators and the anti-complementary activity in the tested Ig preparation was low and, in comparison to seven other commercial i.v. Igs, so was the proportion of IgG polymers and fragments. The IgA content was always 0.02 g/l, often <0.004 g/l, and it was possible to continuously give the Ig prophylactically to four patients with anti-IgA antibodies, i.e. three with CVID and one with combined IgA-IgG2 deficiency. Adverse reactions were only noted in 4.7% of the 1,040 infusions and in 12 out of the 34 patients. None of the reactions were of the anaphylactic type, but two patients had moderate reactions and one had anuria, probably not caused by the Ig. A simultaneous infection seemed to increase the risk of phlogistic reactions, as five out of six patients who reacted with temperature rise and chills had a simultaneous upper respiratory tract infection. A substudy of various dosage schedules was performed with 11 patients receiving 203 infusions over 10.8 patient years. On 25 mg/kg/week of Ig given i.v. every five weeks, a mean increase in the preinfusion serum IgG level of 0.3 g/l was observed, as compared to earlier i.m. prophylaxis with the same dose. Only 1/4 of the patients on 25 mg/kg/week every five or three weeks reached a preinfusion IgG level 3 g/l. On 50 mg/kg/week every two weeks, 4/4 CVID patients had preinfusion levels above 3 g/l with a mean preinfusion increase of 1.5 g/l over the start level. Finally, 100 mg/kg/week every three weeks gave 5/5 patients a preinfusion serum IgG level of >4 g/l with a mean rise of 3.6 g/l, as compared with the levels before the study. An association between decreasing preinfusion IgG serum levels and the presence of infection was noted on 13/17 occasions, while increasing IgG was seen in healthy periods on 14/14 observations.

---

1040 Infusionen mit einem nicht modifizierten Immunglobulin-Produkt, das bei Patienten mit Antikörpermangelsyndrom wenig Nebenwirkungen hervorruft

Zusammenfassung 32 Patienten mit gewöhnlichem variablen Immunglobulinmangel (CVID) und zwei Patienten mit fehlenden IgA- und IgG-Subklassen erhielten zusammen 1040 intravenöse (i.v.) Infusionen innerhalb von 60 Patientenjahren mit 7575 g einer neuen Immunglobulinpräparation (Ig). Der Gehalt an Prä-Kallikrein-Aktivatoren und die anti-komplementäre Aktivität in der getesteten Ig-Präparation war gering, verglichen mit sieben anderen kommerziell erhältlichen i.v. Immunglobulinen. Dasselbe gilt für den Anteil an IgG-Polymeren und -Fragmenten. Der IgA-Gehalt betrug immer 0,02 g/l, oft 0,004 g/l. Das Ig konnte vier Patienten mit IgA-Antikörpern, d. h. drei mit CVID und einem mit kombiniertem IgA-IgG-Mangel kontinuierlich verabreicht werden. Nur bei 4,7% der 1040 Infusionen und bei 12 der 34 Patienten wurden Nebenwirkungen beobachtet. Keine der Nebenwirkungen war vom anaphylaktischen Typ, aber zwei Patienten hatten mittelschwere Nebenwirkungen und einer eine Anurie, die wahrscheinlich nicht durch das Ig verursacht war. Das Risiko für phlogistische Reaktionen schien durch gleichzeitige Infektionen erhöht zu werden. Dies wurde bei fünf von sechs Patienten beobachtet, die bei Infektion der oberen Atemwege auf die Infusion mit Temperaturanstieg und Schüttelfrost reagierten. Bei 11 Patienten, die über 10,8 Patientenjahre 203 Infusionen erhielten, wurde eine Sonderstudie zu verschiedenen Dosierungen durchgeführt. Bei Infusion von 25 mg/kg/Woche i.v. alle fünf Wochen wurde ein mittlerer Anstieg der Serumspiegel vor Infusion gemessen, der um 0,3 g/l höher war als bei früherer i.m. Prophylaxe mit derselben Dosis. Nur bei 1/4 Patienten, die alle fünf oder drei Wochen 25 mg/kg/Woche erhielten, wurde ein IgG-Spiegel vor Infusion von 3 g/l erreicht. Bei Gabe von 50 mg/kg/Woche alle zwei Wochen hatten 4/4 CVID-Patienten vor Infusion Spiegel über 3 g/l, dabei stiegen die Spiegel vor Infusion um 1,5 g/l höher an als vor Therapiebeginn. Bei 100 mg/kg/Woche alle drei Wochen wiesen 5/5 Patienten ein Serum IgG von >4 g/l auf; der mittlere Anstieg gegenüber den Werten vor Studienbeginn betrug 3,6 g/l. Bei 13/17 Fällen wurde eine Assoziation von abnehmenden IgG-Serumspiegeln vor Infusion mit einer Infektion beobachtet; in gesunden Phasen waren bei 14/14 Beobachtungen Anstiege der IgG-Spiegel zu beobachten.

     

Secretory and serum immunoglobulin class-specific antibodies to poliovirus after vaccination

Immune responses in serum and saliva were studied in Pakistani children by enzyme-linked immunosorbent assay after natural exposure to poliovirus and vaccination with live or inactivated poliovirus vaccines. Swedish children unexposed to wild poliovirus who had almost 100% vaccination coverage with inactivated vaccine at 8, 9, and 18 months and at 5 years of age were analyzed for comparison. Natural exposure induced secretory IgA (SIgA) antibodies to poliovirus in the saliva of Pakistani infants at one month of age that reached adult levels at six months. No difference in levels of salivary antibody at eight months was observed between groups vaccinated with either live or inactivated vaccines. Vaccination with live or inactivated vaccine starting at 2 or 3 months of age resulted in high titers of IgG antibody to poliovirus in serum, the highest of which occurred after four doses of live vaccine. In Sweden, an increase of antibody in serum was observed after the third vaccination. IgA antibodies continued to increase subsequently, whereas IgG antibodies reached a plateau. The SIgA response in saliva initially appeared on the third vaccination, with a significant increase after the fourth. Repeated vaccination with inactivated poliovirus vaccine induces specific SIgA antibodies. Adults all had SIgA antibodies to poliovirus in saliva.     

Quantification of mitral valvular incompetence

The hemodynamic and angiographic data of 147 individuals were analyzed in an attempt to assess the value of three techniques used in the diagnosis of mitral incompetence. One hundred patients had clinical evidence of mitral incompetence (group A) and 47 had normal hemodynamics (group B). The degree of mitral incompetence was assessed in all 147 individuals by two methods: determination of a regurgitant index (RI) using indicator dilution curves and determination of a regurgitant fraction (RF) using left ventricular volumes. In 26 patients of group A and 26 individuals in group B mitral incompetence was also assessed by cineangiocardiography. Each of these methods was compared with the clinical and hemodynamic evidence of mitral valvular incompetence. Both the determination of RI by dye dilution curves and RF by angiocardiography were found to be useful in separating normal individuals from patients with mitral valvular incompetence. Severe mitral incompetence is associated with an RI greater than 35% and with an RF greater than 55%. The degree of incompetence by either method was not well correlated with any independent hemodynamic variable. The use of cine angiocardiography to quantify the degree of mitral incompetence was found to be too subjective, depending on the observer, and thus less useful.     

Chemotherapy of visceral leishmaniasis (Leishmania donovani) in the squirrel monkey (Saimiri sciureus)

The relationship of the numbers of amastigotes in the liver to the duration of infection with two lines of a Khartoum strain of Leishmania donovani [designated the parent (P) line and the meglumine antimoniate (Glucantime) resistant (MAR) line] and the effect of meglumine antimoniate on these two lines of Leishmania were studied in the squirrel monkey. All experimental monkeys were inoculated via the saphenous vein with 32.5 X 10(6) amastigotes (per kg body weight), obtained from heavily-infected hamster spleens. Subsequently in Experiment I, liver biopsy samples were taken chronologically from all monkeys. Imprints of liver were made on glass slides and stained with Giemsa's staining solution, and parasite density per gram of liver tissue was determined. The parasites reached a maximum density of 6.2 X 10(6) amastigotes per gram between two to four weeks and 9.4 X 10(7) amastigotes per gram between four to six weeks in the monkeys receiving the P line and the MAR line, respectively. Parasite numbers then decreased, and all the livers and spleens of all monkeys became microscopically negative for Leishmania eight to 13 weeks post-infection. Comparison of the multiplication of the two lines of Leishmania indicated that the MAR line persisted longer in the livers than did the P line. A slight decrease in body weight was observed at eight weeks post-infection. Packed cell volume and haemoglobin were low at four to eight weeks post-infection, but were within the normal range.(ABSTRACT TRUNCATED AT 250 WORDS)     

Problem alcohol use in veterans with mild traumatic brain injury: Associations with cognitive performance and psychiatric symptoms

Introduction: Given that little is known about the associations between alcohol use, cognition, and psychiatric symptoms among veterans with a history of mild traumatic brain injury (mTBI), we aimed to (a) characterize how they differ from veteran controls on a measure of problem drinking; (b) investigate whether problem drinking is associated with demographic or mTBI characteristics; and (c) examine the associations between alcohol use, mTBI history, psychiatric functioning, and cognition. Method: We assessed 59 veterans (n = 32 with mTBI history; n = 27 military controls) for problem alcohol use (Alcohol Use Disorders Identification Test: AUDIT), psychiatric symptoms, and neuropsychological functioning. Results: Compared to controls, veterans with mTBI history were more likely to score above the AUDIT cutoff score of 8 (p = .016), suggesting a higher rate of problem drinking. Participants with mTBI history also showed elevated psychiatric symptoms (ps < .001) and lower cognitive scores (ps < .05 to < .001). Veterans with higher AUDIT scores were younger (p = .05) and had less education (p < .01) and more psychiatric symptoms (ps < .01), but mTBI characteristics did not differ. After controlling for combat and mTBI history (R² = .04, ns) and posttraumatic stress disorder (PTSD) symptoms (ΔR² = .08, p = .05), we found that higher AUDIT scores were associated with poorer attention/processing speed, F(9, 37) = 2.55, p = .022; ΔR² = .26, p = .03. Conclusions: This preliminary study suggested that veterans with mTBI history may be at increased risk for problem drinking. Problem alcohol use was primarily associated with more severe PTSD symptoms and poorer attention/processing speed, though not with combat or mTBI characteristics per se. Importantly, findings emphasize the importance of assessing for and treating problematic alcohol use and comorbid psychiatric symptoms among veterans, including those with a history of neurotrauma.     

Recruitment and PEEP level influences long‐time aeration in saline‐lavaged piglets: an experimental model

Objectives: To evaluate aeration/ventilation in saline‐lavaged piglets during a 3‐h follow‐up after a recruitment maneuver (RM)/PEEP titration compared with PEEP 10 cmH₂O without a RM. Background: Lung recruitment and PEEP titration are used to find a PEEP preventing repetitive opening/collapsing of lung. Methods: Twenty‐one lung‐lavaged piglets, mean age 7 weeks and mean weight 10 kg; a RM‐group and a PEEP10‐group, were ventilated at PEEP 5 cmH₂O (baseline) followed by zero PEEP ventilation. In the RM‐group, tidal elimination of CO₂ and dynamic compliance (Cdyn) guided recruitment and PEEP titration, respectively. A final 3‐h ventilation followed using PEEP 2 cmH₂O above the first decline of Cdyn and end‐inspiratory pressure (EIP) for a target tidal volume (V_T) of 10 ml·kg^?1. In the PEEP10‐group, PEEP 10 cmH₂O without a RM was used during the final 3‐h ventilation. CT scans and blood gases were repeated every 30 min. Airway pressures, Cdyn and hemodynamics were continuously recorded. Results: Aeration improved without differences between groups. The RM‐group PEEP level of 10 ± 0.6 cmH₂O did not differ from the PEEP10‐group. Compared to baseline EIP was lower in the RM‐group after 3‐h ventilation. In both groups, driving pressure (DP) was lower and Cdyn higher than baseline. In the RM‐group, final EIP and DP were lower and Cdyn higher than in the PEEP10‐group. Conclusions: Both RM/PEEP titration and PEEP elevation resulted in improved aeration without differences between groups at the end point. Lung aeration was achieved at lower EIP and DP and higher Cdyn in the RM‐group than in the PEEP10‐group.     

Infectious diseases investment decision evaluation algorithm: a quantitative algorithm for prioritization of naturally occurring infectious disease threats to the U.S. military

Identification of the most significant infectious disease threats to deployed U.S. military forces is important for developing and maintaining an appropriate countermeasure research and development portfolio. We describe a quantitative algorithmic method (the Infectious Diseases Investment Decision Evaluation Algorithm) that uses Armed Forces Medical Intelligence Center information to determine which naturally occurring pathogens pose the most substantial threat to U.S. deployed forces in the absence of specific mitigating countermeasures. The Infectious Diseases Investment Decision Evaluation Algorithm scores the relative importance of various diseases by taking into account both their severity and the likelihood of infection on a country-by-country basis. In such an analysis, the top three endemic disease threats to U.S. deployed forces are malaria, bacteria-caused diarrhea, and dengue fever.