Neonatal adenoviral pneumonia--report of three autopsy cases.

Adenovirus pneumonia, while common in infancy and childhood, is rarely documented but may be fatal in the neonatal period. In regard to the serious outcome and no responsiveness to common anti-viral agents, adenovirus infection should be considered in the differential diagnosis of pneumonia in neonates. We report three cases of fatal neonatal adenovirus pneumonia, all of which were diagnosed by postmortem examination. Two patients were born by cesarean section at 35 or 36 weeks of gestation, and the other was a 5100 gm postmature baby born by vaginal delivery at 43 weeks of gestation. Respiratory insufficiency was detected just after birth or in the immediate postnatal period, and was associated with lethargy and chest X-ray findings of pneumonic infiltration. The postmortem findings of these patients were remarkably consistent and characterized by predominant lung involvement. The lungs showed diffuse massive consolidation with scattered patchy hemorrhage, and histologically revealed multifocal necrotizing alveolitis and/or bronchiolitis, often with hemorrhage. Alveolar lining cells and desquamated cells contained numerous smudge ells and many cells with characteristic inclusion bodies. Electron microscopy revealed that these inclusion bodies consisted of arrays of icosahedral particles of adenovirus. It is unusual that one of the patients, who was born by cesarean section without any evidence of prenatal infection, developed adenoviral pneumonia; this indicates that infection may occur in the immediate postnatal period as well as during passage of the birth canal.     

The Simian Parvoviruses

Autonomous parvoviruses with tropism for erythroid cells have recently been reclassified in a new genus, erythrovirus. Although B19 is the type member, and presently the only internationally accepted member of the erythrovirus genus, we have identified three new simian viruses, all of which have the molecular features of parvoviruses, and are highly tropic for erythroid progenitor cells. This review describes the identification of these new animal parvoviruses and summarises current knowledge of their molecular, clinical and epidemiological features. Most studies have been performed with the first virus discovered, simian parvovirus (SPV), which was isolated from anaemic cynomolgus monkeys. SPV is currently under investigation as an animal model for B19 parvovirus infection. Clinical similarities and molecular homology to parvovirus B19 justify the inclusion of these novel viruses as new members of the erythrovirus genus. © 1997 by John Wiley & Sons, Ltd.     

Antibodies in urine of chimpanzees with chronic adenoviral viruria.

Many chimpanzees have naturally occurring chronic intermittent viruria with an adenovirus of a new type called Pan 11. Small amounts of neutralizing antibodies to Pan 11 adenovirus were found in the urine of chimpanzees. Urinary antibodies to adenovirus were mainly of the immunoglobulin G (IgG) class with some IgA antibodies also present. There was no neutralizing activity in urine against another adenovirus, Pan 9, which has been isolated from lymph nodes, but not from urine, of chimpanzees; however, sera of all chimpanzees had neutralizing antibodies to Pan 9 virus, some with titers similar to those of antibodies against Pan 11 virus. Antibodies reacting with simian cytomegalovirus by indirect immunofluorescence were found in sera of all chimpanzees tested and in two of six urines. There was no correlation between levels of antiviral IgG antibodies in serum and urine by immunofluorescence. These findings suggest that both IgG and IgA antibodies may be locally produced in response to viral infection of the urinary tract in primates.     

Biosafety of adenoviral vectors

Adenoviral vectors can efficiently transduce a broad variety of different cell types and have been used extensively in preclinical and clinical studies. However, early generation of adenoviral vectors retained residual adenoviral genes that contribute to inflammatory immune responses and toxicity. In addition, these vectors often result in transient expression of the potentially therapeutic transgene. Some clinical trials based on early generation adenoviral vectors have been discontinued because of acute inflammatory responses and toxicity and even one patient has died as a direct consequence of adenoviral toxicity. The latest generation of high-capacity adenoviral vectors is devoid of viral genes, and is having a significantly improved safety profile and yielding more prolonged transgene expression compared to early generation vectors. Nevertheless, transgene expression gradually declines even when high-capacity adenoviral vectors are used, possibly due to the gradual loss of vector genomes. Despite their improved safety, high-capacity adenoviral vectors can still trigger transient toxic effects in animals and patients. Restricting the tropism of adenoviral vectors by immunologic or genetic re-targeting may further improve their therapeutic window. The safety of adenoviral vectors has been improved further through the development of safer packaging systems that eliminate the homologous overlap between vector and helper sequences and therefore prevent formation of replication-competent adenoviruses (RCA). RCA could exacerbate inflammatory responses and act as a helper to rescue adenoviral vectors, potentially increasing the effective vector dose. Conditionally replicating adenoviruses (CRAds) have been developed for cancer gene therapy, which replicate selectively in some cancer cells. The use of CRAds in combination with chemotherapy yielded therapeutic effects in patients suffering from cancer but dose-limiting toxicity was apparent. Although there appears to be a very low theoretical risk of malignancy that is predominantly associated with the occurrence of E1-positive recombinants, no malignancies have been reported that were associated with adenoviral vectors. Nevertheless, integrating adenoviral vectors carry a greater malignancy risk due to their ability to integrate randomly into the target genomes.     

Simian retroviruses in African apes

It is now well established that simian immunodeficiency viruses (SIVs) from chimpanzees (SIVcpz) and gorillas (SIVgor) from west Central Africa are at the origin of HIV-1/AIDS. Apes are also infected with other retroviruses, notably simian T-cell lymphotropic viruses (STLVs) and simian foamy viruses (SFVs), that can be transmitted to humans. We discuss the actual knowledge on SIV, STLV and SFV infections in chimpanzees, gorillas, and bonobos. We especially elaborate on how the recent development of non-invasive methods has allowed us to identify the reservoirs of the HIV-1 ancestors in chimpanzees and gorillas, and increased our knowledge of the natural history of SIV infections in chimpanzees. Multiple cross-species events with retroviruses from apes to humans have occurred, but only one transmission of SIVcpz from chimpanzees in south-eastern Cameroon spread worldwide, and is responsible for the actual HIV pandemic. Frequent SFV transmissions have been recently reported, but no human-to-human transmission has been documented yet. Because humans are still in contact with apes, identification of pathogens in wild ape populations can signal which pathogens may be cause risk for humans, and allow the development of serological and molecular assays with which to detect transmissions to humans. Finally, non-invasive sampling also allows the study of the impact of retroviruses and other pathogens on the health and survival of endangered species such as chimpanzees, gorillas, and bonobos.     

Idiopathic bronchiolocentric interstitial pneumonia.

The authors report 10 patients with a distinctive idiopathic bronchiolocentric interstitial pneumonia having some histologic similarities to hypersensitivity pneumonitis. Bronchiolocentric interstitial pneumonia has a marked predilection for women (80%) and occurs in middle age (40-50 years). Chest radiographs and pulmonary function tests show interstitial and restrictive lung disease, while the histologic appearance is that of a centrilobular inflammatory process with small airway fibrosis and inflammation that radiates into the interstitium of the distal acinus in a patchy fashion. Granulomas are not identified. At a mean followup of approximately 4 years in nine patients, 33% of patients were dead of disease and 56% had persistent or progressive disease suggesting a more aggressive course than hypersensitivity pneumonitis and nonspecific interstitial pneumonia, the two major disease processes in the differential diagnosis. Whether Bronchiolocentric interstitial pneumonia is a unique entity or not, the pattern of bronchiocentric injury to the lung in the absence of known causes and its clinical presentation as interstitial lung disease, warrants further investigation of this unusual interstitial process.     

Bronchoscopic diagnosis of pneumonia.

Lower respiratory tract infections are characterized by significant morbidity and mortality but also by a relative inability to establish a specific etiologic agent on clinical grounds alone. With the recognized shortcomings of expectorated or aspirated secretions toward establishing an etiologic diagnosis, clinicians have increasingly used bronchoscopy to obtain diagnostic samples. A variety of specimen types may be obtained, including bronchial washes or brushes, protected specimen brushings, bronchoalveolar lavage, and transbronchial biopsies. Bronchoscopy has been applied in three primary clinical settings, including the immunocompromised host, especially human immunodeficiency virus-infected and organ transplant patients; ventilator-associated pneumonia; and severe, nonresolving community- or hospital-acquired pneumonia in nonventilated patients. In each clinical setting, and for each specimen type, specific laboratory protocols are required to provide maximal information. These protocols should provide for the use of a variety of rapid microscopic and quantitative culture techniques and the use of a variety of specific stains and selective culture to detect unusual organism groups.     

Fatal Legionella maceachernii pneumonia.

Legionella maceachernii, previously isolated only from the environment, was shown to be a cause of fatal pneumonia in an immunocompromised patient.     

Journal Club. HIV-associated bacterial pneumonia

Bacterial pneumonia is the most common cause of death from pneumonia in patients with HIV disease, causing greater mortality than Pneumocystis carinii pneumonia. The challenge for the clinician evaluating the HIV-infected patient with pneumonia is to quickly distinguish clinically among all possible causes and to initiate therapy based on the most likely diagnosis. While an understanding of typical clinical and radiographic presentations is essential, bronchoscopy is the preferred test for reliably identifying the causative organism.     

Fatal adenoviral hepatitis after rituximab therapy

Rituximab is an anti-CD20 monoclonal antibody used in the treatment of B-cell proliferative disorders. Although it is very effective in many cases, a number of case reports in the literature have described fatal viral reactivations associated with rituximab therapy. We report what is to our knowledge the first case of fatal adenoviral hepatitis in a patient with Waldenstrom macroglobulinemia treated with rituximab. This case is a new example of an emerging pattern of association between rituximab therapy and fatal viral reactivations, and it urges increased vigilance when using rituximab-based treatment regimens.     

Complement levels in pneumococcal pneumonia.

Levels of complement proteins and functional activity of the alternate complement pathway were assessed in 39 patients with pneumococcal pneumonia. Mean levels of C3 and properdin and the functional activity of the alternate pathway in acute sera were significantly (P less than 0.05) below normal, whereas levels of components of the early classical pathway were normal. Although levels of factor B were in the normal range, they correlated significantly with C3 levels; there was no significant relation between C3 levels and C4 or C1q levels. The 19 patients iwth pneumococcal pneumonia and bacteremia had significantly lower mean values of properdin and factor B than the 20 patients without bacteremia, suggesting a more severe depression of the alternate complement pathway with bacteremia. During convalescence, complement levels were normal or elevated in most of the patients, but mean levels of properdin remained significantly below normal in bacteremic patients. Functional activity of the alternate pathway also remained below normal. These results indicate that there is a selective depression of the alternate pathway in patients with pneumococcal pneumonia, and they are consistent with the concept that the alternate pathway has an important role in host defenses in pneumococcal infection.     

Advances in helper-dependent adenoviral vector research

The immunogenicity and cytotoxicity associated with early generations of adenoviral vectors provided a strong incentive for the development of helper-dependent adenovirus, a last generation of adenoviral vectors that is devoid of all viral coding sequences. These vectors have shown to mediate longer high-level transgene expression in vivo with reduced toxicity and thus offer enormous potential for human gene therapy. In addition, they possess a considerably larger cloning capacity than conventional adenoviral vectors making the transfer of large cDNAs, multiple transgenes and longer tissue-specific or regulable promoters possible. In this article, we review the progress made with helper-dependent adenoviral vectors. The development and optimization of scalable production processes and strategies for helper removal will be presented. Current chromatography options available for vector purification and the new challenges facing researchers for the separation of empty particles and/or helper viruses will be discussed. Finally, we will describe recent advances made in our understanding of their interaction with the immune system and their potential as gene delivery vehicles in vivo for the treatment of diseases affecting liver, skeletal muscle and brain.