The development of the human immune system begins early during embryogenesis and occurs in phases that sequentially enable the establishment of self-tolerance by the adaptive immune system, protection of newborns from potential microbial threats, as well as avoidance of over-exuberant inflammation upon post-natal colonization. The immune system of newborns is thus immunologically distinct, with variable deficits compared to adults, depending on the gestational age.

Discriminating between patients with microbial infections that cause secondary immune effects from those with the same infection who have primary immune deficiency disease can be difficult. There are many microbes that temporarily “stun” innate and/or adaptive immunity during a primary infection. The common result of temporary inhibition, or permanent depletion of host immunity during some primary infections is the development of superinfections of other microbes that cause significant morbidity, and on occasion, mortality. In addition, microbes that cause persistent infection, such as the human immune deficiency virus, deplete effective immunity over time and can also lead to secondary infections with other microbes ultimately leading to death if not appropriately treated. In some cases, such as influenza virus infection, mortality can be dramatic due in large part to acquired secondary bacterial infections. Many microbes manipulate host immunity and thereby inhibit the ability of patients to combat secondary microbial infections. The overall survival of patients primarily infected with some viruses, parasites, or bacteria, is closely linked to the ability of secondary infections to take advantage of the immune modulation induced by the primary infection. Herein we discuss some of the secondary immune defects caused by select viruses (measles, influenza, HIV1, HTLV), parasites, (leishmania, malaria), and bacteria (Bordetella pertussis). Furthermore, the genetic susceptibility of a given host to become infected, or develop severe disease, also determines whether an infected individual who becomes infected with a secondary microbe survives. Future studies are needed to explore not only the immunomodulation caused by select microbes, but also the repertoire of immune responses expressed by infected individuals in order to predict clinical outcomes of these infections. Thus, understanding the delicate balance that exists between “immune altering” microbes that suppress immune responses during primary infections leading to severe secondary infections versus those infections found in patients with inborn errors of innate or adaptive immunity, is essential in predicting the clinical outcome and the appropriate treatment for these two different patient populations.

Protein loss is a recognized cause of hypogammaglobulinemia and lymphatic loss appears in nearly every differential diagnosis of low T cells, yet, the practical approach to identification and management of these conditions is poorly studied. This chapter approaches the topic from the setting of an immunologist called to dissect the mechanism and management.

Transplantation of thymic tissue was initially attempted in the 1960s and 1970s. Long-term successes were rare but these studies served as an important foundation. Today, cultured thymus tissue transplantation (CTTT) is performed for athymic infants. Almost all CTTT recipients are infants with complete DiGeorge anomaly. CTTT is an investigational product regulated by the FDA. Duke is only center in the United States performing thymus transplantation and this chapter reviews the experience to date.

The modern recognition of defects in host defense and the dawn of the field of primary immune deficiencies was catalyzed by the advent of instrumentation capable of identifying immunoglobulins. Congenital agammaglobulinemia was originally identified by Colonel Ogden Bruton through the analysis of the electrophoretic pattern of serum proteins. Over the past 6+decades since Bruton's seminal report, advances in understanding and enhanced laboratory tools for evaluating the immune system have led to the identification of an expanding number of immune deficiency disorders (PIDD). At present the diagnosis and management of primary immune deficiencies relies heavily on laboratory analysis of immune cells and proteins. This chapter will discuss typical analytic methods used to study the immune system exclusive of genetic testing, which will be covered in Chapter 5.

Many resources continue to evolve for the modern clinical immunologist taking care of patients with primary immunodeficiency diseases, and also for those researching these rare diseases. Resources include websites, professional and patient organizations, interactive search tools, databases, and list serves. This chapter offers an overview of many of the resources available today. The chapter is divided into sections covering professional organizations, registries, clinical/diagnostic tools (including the rapidly evolving genetic testing/interpretation category), research, and advocacy/patient organizations. Many of the websites share links with each other, and point to other important and useful resources not covered in detail here.

Primary immune deficiencies are often considered to have a prominent infectious phenotype. Indeed, this is often the case and historically, susceptibility to infection was one of the hallmarks of immune deficiencies. Nevertheless, there has always been an undercurrent of autoimmunity and inflammation. This chapter will discuss the conditions where autoimmunity is the dominant or in some cases, the only manifestation of an immune system gone awry. These conditions, along with those where atopy is the major manifestation and the conditions associated with hemophagocytic lymphohistiocytosis constitute the immune dysregulation conditions.

Neutrophils are the main cellular component of the innate immune system, and defects in their functions will thus lead to increased susceptibility of infections. Essential for their function is their ability to adhere to the endothelial blood vessels and to migrate to site of infections. This chapter will discuss the various defects found in migration. Although, all these conditions are rare, some are more common. Leukocyte adhesion deficiency (LAD) type 1 has been reported in hundreds of patients worldwide, while some of the chemotaxis defects have been described in a single patient. For most of the syndromes the molecular defect has been revealed and thus a more appropriate approach to therapy can be given. In some cases the only curative treatment is hematopoietic stem cell transplantation while in other cases antibiotics alone can be enough. Recently, biological agents as well as gene therapy showed beneficial results in some cases.

Asplenia and splenic hypoplasia refer to the complete or partial lack (or function) of splenic tissue. Asplenia can be congenital, functional (as in sickle cell anemia), or acquired after trauma or surgery. Congenital asplenia is a rare life-threatening condition, often presenting with pneumococcal sepsis. It may arise as part of situs abnormalities or result from a specific defect of spleen development. Most of the reported cases are familial and the mode of inheritance is usually autosomal dominant. In addition, a wide range of diseases can affect the function of the spleen, including metabolic, autoimmune, infectious and hematological disorders. The spleen plays an important role in the defense against pathogens and immune-homeostasis. Its rich and diverse population of immune cells and its anatomy enables optimal surveillance and phagocytosis of circulating blood elements. Moreover, the spleen is crucial in humoral response to polysaccharides, including antigens of encapsulated bacteria. For patients suspected to have splenic impairment, it is important to quantify the splenic function in order to assess the risk of developing overwhelming post-splenectomy syndrome and thromboembolic events. The prevention and treatment of these complications are described in this chapter.

Idiopathic CD4 lymphopenia (ICL) is a heterogeneous syndrome characterized by low CD4 T lymphocyte counts at <300cells/μL on at least two occasions in the absence of a known infection or intercurrent illness. The clinical manifestations of ICL vary greatly, from asymptomatic lymphopenia to severe opportunistic disease, autoimmunity, or neoplasia (frequently related to persistent viral infections). Most common infections reported in ICL include cryptococcal disease, human papilloma, and herpes zoster viruses. The diagnosis of ICL requires exclusion of genetic immune deficiencies and other hematologic diseases or infections, and confirmation of low CD4 lymphocyte counts. Although cytokine therapies and allogeneic stem cell transplantation have been rarely used with variable success, there is currently no specific therapy for ICL. Treatment of underlying infections and antibiotic prophylaxis are the mainstay of available therapy of ICL. A better understanding of the etiology, pathogenesis, and prognosis of ICL will assist in improved therapeutic approaches.