Prenatal cytomegalovirus, rubella, and Zika virus infections associated with developmental disabilities: past, present, and future.

Prenatal infections have long been recognized as important, preventable causes of developmental disabilities. The list of pathogens that are recognized to have deleterious effects on fetal brain development continues to grow, most recently with the association between Zika virus (ZIKV) and microcephaly. To answer clinical questions in real time about the impact of a novel infection on developmental disabilities, an historical framework is key. The lessons learned from three historically important pathogens: rubella, cytomegalovirus, and ZIKV, and how these lessons are useful to approach emerging congenital infections are discussed in this review. Congenital infections are preventable causes of developmental disabilities and several public health approaches may be used to prevent prenatal infection. When they cannot be prevented, the sequelae of prenatal infection may be treatable. WHAT THIS PAPER ADDS: The list of prenatal infections associated with developmental disabilities continues to increase. Lessons learned from rubella, cytomegalovirus, and Zika virus have implications for new pathogens. Severity of illness in the mother does not correlate with severity of sequelae in the infant.

Congenital Cytomegalovirus-History, Current Practice, and Future Opportunities.

Cytomegalovirus (CMV) was first identified in the 1950s and noted to cause newborn disease in the 1960s. It is now known to be the most common cause of congenital infection in the world, leading to various central nervous system sequelae, the most common being hearing loss. Cytomegalovirus is a ubiquitous pathogen that affects nearly 30,000 infants annually in the United States, leading to 3,000-4,000 cases of hearing loss. Prevention through vaccination has proved unreliable, as has the use of immune globulin. Prevention through education has been shown to be the most effective method of minimizing infection. Antiviral therapy is effective at reducing the impact of infection on newborns. Continued global efforts will hopefully provide more solutions for this opportunistic infection.

Infection and atherosclerosis. An alternative view on an outdated hypothesis.

Already at the beginning of the 20th century, a potential role for microbes in vascular diseases was suggested. However, until the late '70 of that century, not much attention has been paid to this infection hypothesis. Then, predominantly based on the pioneering work of Fabricant et al., evidence for a contributing or even initiating role for microbes in atherosclerosis, as well as other vascular diseases, was accumulating. Also, the seminal paper by Saikku and co-workers, demonstrating serological evidence of an association of Chlamydia pneumoniae, an obligate intracellular respiratory gram-negative bacterium, with chronic coronary heart disease and acute myocardial infarction, significantly boosted the research on the infection hypothesis. Since then, numerous papers have been published demonstrating associations between a large variety of pathogens and atherosclerotic disease. Furthermore, many molecular mechanisms have been suggested by which microbes may affect atherogenesis. Nevertheless, in recent large randomised prospective trials, evaluating the efficacy of antibiotic treatment for the secondary prevention of coronary events, no reduction in the rate of cardiovascular events was observed, thereby seriously challenging the validity of the infection hypothesis. Nevertheless, the large body of supporting evidence, which has accumulate over the past decades, should not be ignored and maybe we should look at the hypothesis, and in particular the mechanisms by which microbes affect the disease, from a different angle.

The history of cytomegalovirus and its diseases.

Intranuclear inclusions typical of cytomegalovirus infections were first noticed in 1881 by German scientists who thought they represented protozoa. After viruses were grown in cell cultures, Weller, Smith and Rowe independently isolated and grew CMV from man and mice in 1956-1957. Antibodies in 30-100% of normal adults indicate not only a past infection, but the presence of a present latent infection. The presence of CMV DNA in tissues and most organs surveyed indicates the ubiquity of latent infection. CMV disease requires the virus and some deficiency of immunity such as occurs in the immature fetus, in AIDS, and in transplant patients on immunosuppressive drugs. Antiviral agents can inhibit CMV replication but they cannot prevent or cure latent infections. A pharmacological approach using the many leads in understanding latency is needed.

Transmission or recurrence? A historical dilemma of iatrogenic infections due to cytomegalovirus.

This article traces the changes in thought regarding the etiology of iatrogenic infections due to cytomegalovirus from the 1960s to the 1990s. Initial investigations using serologic and culture methods focused on how the virus was acquired. Following the application of molecular tools, theories on disease causality expanded beyond concerns of the microorganism itself to include aspects of the virus-host interaction and the host response. Eventually, the insights gained from the investigations into the etiology of iatrogenic cytomegalovirus disease were applied to other intracellular viruses. In addition, recognition of the factors responsible for reactivation of latent viruses had not only theoretical value, but also practical consequences.

History of the cytomegalovirus.

Because it is capable of producing both congenital and acquired infections, the cytomegalovirus (CMV) has become an extremely important pathogen, and review of its history is pertinent. Inclusion-bearing cells were first shown by Ribbert in 1881. Goodpasture and Talbert in 1921 were the first to suggest that the "cytomegalia" could be due to a viral agent. In 1950, Smith and Vellios showed that infection may occur in utero. The introduction of exfoliative cytology methods allowed identification of characteristic cells in the urine of infected infants. Smith in 1956, Rowe and coworkers in 1956, and Weller et al in 1957 independently isolated human CMV strains. In 1960, Weller and coworkers proposed the term "cytomegalovirus" and subsequently isolated CMV from the urine of infants with generalized disease. CMV has now become one of the most common opportunistic pathogens encountered in patients immunocompromised from congenital or acquired causes such as AIDS or transplantation procedures.

[Albert Jesionek tracking cytomegalovirus disease]. / Albert Jesionek auf der Spur der Zytomegaliekrankheit.

The first publications concerning the peculiar cellular structures that later-on became the hallmark of cytomegalic inclusion disease, originated in the early 20th century from German institutes. These early reports got into oblivion even before their significance and implications could be fully realized. The purpose of this study is to reconsider the contributions of Jesionek and other authors to the discovery of the "protozoa-like structures", based upon their publications and in accordance with the state of knowledge at that time.

[Tietze and cytomegalovirus infection of the salivary glands]. / Tietze und die Zytomegalie-Erkrankung der Speicheldrüsen.

Tietze has observed in 1898 the presence of peculiar huge cells in a tumor excised from the parotid gland of an infant. He held the structures for protozoan parasites immigrated from the oral cavity, but they turned out to be cytomegalic inclusion cells. Hence, the first description of cytomegaly-associated symptomatic illness dates back to Tietze's paper. It appears that he was the first author to establish the diagnosis in vivo, and his patient was the first one reported having survived this disease.

Citomegalovirose / Cytomegalovirus Disease

As infecçöes por CMV vêm assumindo papel de destaque cada vez maior em imunodeprimidos tais como pacientes com AIDS, transplantados renais e outros com déficit da imunidade celular. Também o CMV é considerado a causa mais comum de infecçäo congênita. Objetivamos com esta revisäo abordar os aspectos gerais das citomegaloviroses: histórico, características do vírus, patogênese, epidemiologia, incidência, quadro clínico, métodos diagnósticos e tratamento. Com isso, pretendemos ressaltar a importância desta infecçäo, que tem frequência subestimada devido a dificuldades diagnósticas e às vezes pelo desconhecimento de suas características. O diagnóstico da citomegalovirose propicia ao clínico tomada de medidas tais como: evitar uso abusivo de antibióticos em casos de febre prolongada, seleçäo de doadores de sangue e ou órgäos, detecçäo das crianças com infecçäo congênita e das gestantes de risco, assim como o uso de drogas antivirais específicas em pacientes imunodeprimidos

Doença de inclusão citomegálica: contribuição ao estudo clínico e patológico / Cytomegalic inclusion disease: contribution to the clinical and pathological study

Foi feito um estudo retrospectivo de trinta casos de doença de inclusão citomegálica, dentre 83, diagnosticados microscopicamente pelo serviço de anatomia patológica do Hospital Universitário Antonio Pedro, no período de 1970 a 1989. O diagnóstico foi confirmado pela presença da célula de inclusão típica em vários órgãos. A seleção dos pacientes foi feita pela disponibilidade dos prontuários clínicos. Seis crianças eram recém-nascidas, 21 tinham menos de seis meses, e três mais de seis meses. Sete eram prematuros. Os achados clínicos mais freqüentes foram distúrbios respiratórios (60%), hepatomegalia (60%), diarréia protraída (53%), desnutrição (peso abaixo do percentil 2,5 - 46%), esplenomegalia (30%) e insuficência cardíaca congestiva (16,6%). Exantema petequial ocorreu em apenas dois recém-nascidos. Somente quatro crianças foram investigadas laborarorialmente para a doença. Concluiu-se que a forma clássica descrita em recém-nascidos não foi comum e que a doença de inclusão citomegálica deve ser considerada no diagnóstico diferencial daqueles lactentes que apresentem pneumonite associada à diarreia protraída ou a colestase.