Dengue viruses occur as four antigenically related but distinct serotypes transmitted to humans by Aedes aegypti mosquitoes. These viruses generally cause a benign syndrome, dengue fever, in the American and African tropics, and a severe syndrome, dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), in Southeast Asian children. This severe syndrome, which recently has also been identified in children infected with the virus in Puerto Rico, is characterized by increased vascular permeability and abnormal hemostasis. It occurs in infants less than 1 year of age born to dengue-immune mothers and in children 1 year and older who are immune to one serotype of dengue virus and are experiencing infection with a second serotype. Dengue viruses replicate in cells of mononuclear phagocyte lineage, and subneutralizing concentrations of dengue antibody enhance dengue virus infection in these cells. This antibody-dependent enhancement of infection regulates dengue disease in human beings, although disease severity may also be controlled genetically, possibly by permitting and restricting the growth of virus in monocytes. Monoclonal antibodies show heterogeneous distribution of antigenic epitopes on dengue viruses. These epitopes serve to regulate disease: when antibodies to shared antigens partially neutralize heterotypic virus, infection and disease are dampened; enhancing antibodies alone result in heightened disease response. Further knowledge of the structure of dengue genomes should permit rapid advances in understanding the pathogenetic mechanisms of dengue.

https://science.sciencemag.org/content/sci/239/4839/476.full.pdf

Pathogenesis of dengue: challenges to molecular biology

Influenza viruses are significant human respiratory pathogens that cause both seasonal, endemic infections and periodic, unpredictable pandemics. The worst pandemic on record, in 1918, killed approximately 50 million people worldwide. Human infections caused by H5N1 highly pathogenic avian influenza viruses have raised concern about the emergence of another pandemic. The histopathology of fatal influenza virus pneumonias as documented over the past 120 years is reviewed here. Strikingly, the spectrum of pathologic changes described in the 1918 influenza pandemic is not significantly different from the histopathology observed in other less lethal pandemics or even in deaths occurring during seasonal influenza outbreaks.

The Pathology of Influenza Virus Infections

Cultured mononuclear peripheral blood leukocytes (PBL) from nonimmune human beings and monkeys are nonpermissive to dengue 2 virus (D2V) infection at multiplicities of infection of 0.001-0.1, but become permissive when non-neutralizing dengue antibody is added to medium. D2V infection occurred in PBL prepared from anti-coagulated but not from defibrinated plasma. Infection enhancement was produced by multiple lots of heterotypic anti-dengue raised in several mammalian species. Homotypic anti-dengue neutralized D2V at high concentrations but enhanced at low concentrations; enhancement end point in one serum was 1:320,000. The infection-enhancing factor was a noncytophilic antibody of the IgG class. D2V infection occurred in the absence of heat-labile complement components but did not occur when complexes were prepared with anti- dengue F(ab)(2). Treatment of PBL with several proteases increased permissiveness to D2V infection by immune complexes but not by virus alone. Two rhesus monkey serums collected 14 days after D2V infection contained an IgG antibody with high-titered enhancing activity but with no hemagglutination-inhibition or neutralizing activity. Virus-antibody complexes are irreversibly attached to PBL within 15 min and completely internalized in 60 min. There was considerable variation in cellular infection in different experiments, however, maximum virus yields usually exceeded 1,000 plaque-forming units per 1 x 10(6) PBL occurring between 2 and 4 days in culture. In vitro antibody-dependent infection of PBL provides a possible model for study of pathogenetic mechanisms in infants with dengue shock syndrome who passively acquire maternal anti-dengue IgG.

/pdf/dengue-viruses-and-mononuclear-phagocytes-i-infection-52g9m6opwy.pdf

Dengue viruses and mononuclear phagocytes. I. Infection enhancement by non-neutralizing antibody.

Influenza virus evolution, host adaptation, and pandemic formation.

A sensitivie and simple procedure for the detection and quantitation of soluble complement (C)- fixing immune complexes in sera of patients with various disease states has been developed by utilizing C receptors on Raji cells. These cells lack membrane-bound immunoglobulin but have receptors for IgG Fc, C3b, C3d, and possibly with other C proteins. Uptake experiments showed that both aggregated human gamma globulin (AHG) and 7S IgG bound to receptors for IgG Fc; however, AHG reacted with C bound to cells only via receptors for C and this binding was much more efficient than via IgG Fc receptors. AHG was used as an in vitro model of human immune complexes and its uptake by Raji cells was quantitated by 125I-radiolabeled antihuman IgG. The limit of sensitivity of this test was 6 mug AHG/ml serum. The ability of Raji cells to detect AHG in serum depended on the amount of radioactive antibody used and the size of aggregates. The presence of an excess of C somewhat inhibited binding of AHG containing C to Raji cells. The efficient binding of AHG by receptors for C on Raji cells was used for the detection and quantitation of immune complexes in human sera. Raji cells were incubated with sera to be tested and then reacted with excess radiolabeled antihuman IgG; the amount of radioactivity bound to the washed cells was determined and referred to a standard curve of radioactive antibody uptake by cells previously incubated with increasing amounts of AHG in serum. Thereby immune complexes were detected and quantitated in serum hepatitis, systemic lupus erythematosus, vasculitis, subacute sclerosing panencephalitis, dengue hemorrhagic fever, and malignancies.

/pdf/the-raji-cell-radioimmune-assay-for-detecting-immune-7f243uhdgp.pdf

The Raji cell radioimmune assay for detecting immune complexes in human sera.

In Bangkok, Thailand, 49 of 127 patients with dengue hemorrhagic fever experienced shock. The concentration of nine complement proteins measured in serial serum samples decreased during shock with the exception of C9. C3 and C5 were reduced to 20 to 40 per cent of normal in severe cases. Decrease of plasma fibrinogen, appearance of fibrinogen split products and thrombocytopenia indicated occurence of intravascular coagulation. Metabolic studies of C3 and C1q, performed on 24 patients, indicated a markedly enhanced fractional catabolic rate especially during shock. These results support the concept that activation of complement can constitute a major factor in the pathogenesis of dengue hemorrhagic shock. (N Engl J Med 289:996–1000, 1973)

The potential pathogenic role of complement in dengue hemorrhagic shock syndrome.

Selective gastrointestinal infection without illness was induced in susceptible volunteers by oral administration of enteric-coated capsules containing live adenovirus type 7 (ADV-7). This vaccine was found similar to the live, oral adenovirus type 4 (ADV-4) vaccine in safety, infectivity, restriction of induced infection to the intestinal tract, and lack of transmission of vaccine virus from infected vaccinees to susceptible close contacts. Specific neutralizing antibody was stimulated in over 95% of infected volunteers by 21 days after immunization and levels of antibody were similar to levels of specific neutralizing antibody induced by the ADV-4 vaccine. Simultaneous administration of ADV-4 and ADV-7 vaccines was found to be safe and to stimulate neutralizing antibody to both viruses in 10 of 12 volunteers immunized. These studies suggest that live ADV-7 vaccine, given alone or with the ADV-4 vaccine, may be useful in the prevention of type-specific adenovirus disease in populations of military trainees.

Immunization with Live Types 7 and 4 Adenovirus Vaccines. I. Safety, Infectivity, Antigenicity, and Potency of Adenovirus Type 7 Vaccine in Humans

Despite its relatively common occurrence in infants and young children, fatal pneumonia associated with adenovirus Type 7 (ADV-7) in previously healthy adults appears to be very rare. We observed three fatal cases in young male adults, previously in good health, while they were undergoing Army basic training. Each case was associated with absolute lymphopenia and followed a similar clinical course. In the terminal stages, multisystem disease, including disseminated intravascular coagulation, developed in all three. Post-mortem findings revealed extensive pulmonary damage, with bronchial epithelial necrosis, interstitial alveolar thickening and hyaline membranes; small vessels contained hyaline thrombi. ADV-7 was recovered from the upper respiratory tract of each man shortly after hospitalization and again, in high titer, from lung tissue obtained after death. Serum specimens obtained before death revealed high titers of ADV-7 neutralizing antibody.

Fatal pneumonia associated with adenovirus type 7 in three military trainees.

Background.Respiratory syncytial virus (RSV) is the leading cause of lower respiratory disease in infants and children. MEDI-493 (palivizumab, Synagis®) is a humanized monoclonal IgG1 antibody to the fusion protein of RSV, and it is highly active in vitro against RSV A and B strains.Objective.To des

Safety and pharmacokinetics of an intramuscular humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia

In early 1976, the novel A/New Jersey/76 (Hsw1N1) influenza virus caused severe respiratory illness in 13 soldiers with 1 death at Fort Dix, New Jersey. Since A/New Jersey was similar to the 1918-1919 pandemic virus, rapid outbreak assessment and enhanced surveillance were initiated. A/New Jersey virus was detected only from January 19 to February 9 and did not spread beyond Fort Dix. A/Victoria/75 (H3N2) spread simultaneously, also caused illness, and persisted until March. Up to 230 soldiers were infected with the A/New Jersey virus. Rapid recognition of A/New Jersey, swift outbreak assessment, and enhanced surveillance resulted from excellent collaboration between Fort Dix, New Jersey Department of Health, Walter Reed Army Institute of Research, and Center for Disease Control personnel. Despite efforts to define the events at Fort Dix, many questions remain unanswered, including the following: Where did A/New Jersey come from? Why did transmission stop?

/pdf/swine-influenza-a-outbreak-fort-dix-new-jersey-1976-4dfh1gfung.pdf

Franklin H. Top

Papers

The potential pathogenic role of complement in dengue hemorrhagic shock syndrome.

Immunization with Live Types 7 and 4 Adenovirus Vaccines. I. Safety, Infectivity, Antigenicity, and Potency of Adenovirus Type 7 Vaccine in Humans

Fatal pneumonia associated with adenovirus type 7 in three military trainees.

Safety and pharmacokinetics of an intramuscular humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia

Swine influenza a outbreak, Fort Dix, New Jersey, 1976.