If diagnosed in a timely fashion and monitored adequately, patients with primary immunodeficiency diseases (PIs) infrequently require hospitalization for treatment of infections, flares of autoimmunity, and rarely, management of cancer. The greatest challenge is making an expeditious diagnosis of a PI. Initial evaluation often occurs during a hospitalization for prolonged, severe, or recurrent infections. Occasionally, illnesses due to unusual pathogens raise suspicion for an underlying immunodeficiency. Thus increased awareness of the key features of PIs not only assists in management of these children when admitted, but also helps the pediatric hospitalist identify children at risk for PI. In most cases, these children benefit when the hospitalist can promptly initiate appropriate laboratory studies and obtain consultation from a pediatric immunologist.

HISTORY

Prompt identification of children with a PI is paramount to reduce the risk of irrevocable sequelae of invasive infections, such as bronchiectasis, encephalitis, or kidney failure. Establishing a set of clear warning signs that indicate a PI has been challenging because of the subjective nature of what constitutes a “severe” infection or exactly what pattern constitutes “recurrent” infections. To address this concern, the Jeffrey Modell Foundation worked with experts on a list of 10 warning signs (Table 49-1), the presence of two or more of which should raise suspicion of PI. Of note, these warning signs largely emphasize infections as a core feature of PI. Two recent analyses found these 10 warning signs fail to identify many subjects with PIs.^1,2 Missing from this list are features of defective tolerance, including autoimmune and allergic diseases, and malignancies. Furthermore, the need for intravenous antibiotics, failure to thrive, or a relevant family history were recently found to be the strongest predictors of PI.^3,4

To address the complexity of evaluating the suspicion for PI, multi-step flow charts have been developed to facilitate early identification by screening patients based on history and physical examination.^5,6

A recent success in the early detection of patients with severe PI was the development of a qPCR-based assay that gauges post-thymic T-cells, which identifies newborns with T-cell lymphopenia such as in severe combined immunodeficiency (SCID). A newly established program to screen newborns with this assay now evaluates almost all newborns in the United States. Patients flagged by this assay may possess biologically relevant defects of immunological pathways, and can be identified long before they have any typical warning signs or classical “immunological phenotypes,” such as opportunistic infections. Children flagged by this screen may simply be premature; the number of T-cells increases through gestation. The screen often flags patients with partial DiGeorge syndrome as well. Furthermore, with the prospect of broad sequencing–based screening methods around the corner, we can expect in the future to identify a wide array of novel specific gene defects among PI patients that may allow mechanism-based intervention with biological compounds or early utilization of definitive treatment (e.g. hematopoietic stem cell transplantation [HSCT] or gene therapy). Without specific laboratory workup, general diagnostic tests are limited in predicting the risk for serious infections or autoimmune diseases among susceptible patients. To identify these patients early, clinicians should maintain increased vigilance for hallmark signs of PIs based on a detailed clinical history of increased susceptibility to infections, autoimmunity, inflammation, or cancer. We cover each of these areas next.

SUSCEPTIBILITY TO INFECTION

Pediatric hospitalists should be aware than increased susceptibility to infections is the main hallmark of PIs. Infections can be severe, invasive, and/or recurrent. Opportunistic organisms are not uncommon in situations where cellular immunity or innate defenses are compromised. In infancy, infections may not be apparent in the first few months of life due to protection from transplacental transfer of IgGs from the mother, mostly during third trimester. Infants with defects of innate or T-cell immunity may present with local or disseminated infection from the Mycobacterium bovis Bacille Calmette-Guerin vaccine strain (“BCGosis”) in countries outside the United States where this vaccine is employed. Similarly, severe diarrheal illnesses have been described in SCID patients due to vaccine-strain rotavirus. Severe encephalitis in infancy due to HSV-1 may be indicative of defects of the innate TLR3 pathway. Severe candidal infections have been described in infants with defects of tolerance due to impaired selection of T-cells in the thymus (e.g. in autoimmune polyendocrinopathy, candidiasis, ectodermal dysplasia [APECED]), due to dysfunction of regulatory T-cells (immunodeficiency, polyendocrinopathy, enteropathy X-linked [IPEX]), due to deficiency of CARD9, due deficiencies of the IL-12 signaling axis, due to deficiency of IL-17RA or IL-17F, or due to gain-of-function mutations in STAT1.

Outside of infancy, older children and young adults may present with bacterial, viral, yeast, and fungal infections. Any serious, invasive infection in a child should at least trigger consideration of an immune defect, especially if it involves an opportunistic pathogen.

SUSCEPTIBILITY TO AUTOIMMUNITY

Autoimmunity is increasingly noted either as a presenting sign of PI or as a complication. It poses a great challenge to specialists, as autoimmunity in PI often resists conventional treatments. Autoimmune manifestations can broaden with time, and flares may be triggered by infections.

Curiously, the generation of autoreactive cells is a natural phenomenon, but mechanisms of central and peripheral tolerance attenuate these cells at specific checkpoints of T- and B-cell development. In PI, the immune defect may impair these checkpoints and allow for the accumulation of autoreactive cells, priming the patient ultimately for development of clinical autoimmune disease.

In PI, autoimmune cytopenias (e.g. immune thrombocytopenia, autoimmune hemolytic anemia, and autoimmune neutropenia) are the most commonly seen autoimmune disorders. Any patient with autoimmune cytopenias who has a prolonged and complicated course or insufficient response to conventional therapy should be considered for evaluation of PI.

Autoimmune cytopenias can be present in over 10% to 30% of the cases of the most common PI, common variable immunodeficiency (CVID), which is characterized by insufficient production of immunoglobulins (low IgG along with low IgA or IgM), poor specific responses to vaccinations, and (typically) recurrent sino-pulmonary infections. It is not uncommon that CVID patients will present with an autoimmune cytopenia and later develop a full-blown CVID immunological phenotype. Furthermore, vitiligo has recently been associated with new genetic defects of CVID.⁶ Autoimmune cytopenias reflect B-cell dysregulation and therefore can be present in a wide variety of PIs where B- and T-cell tolerance is impaired such as in APECED, IPEX, or autoimmune lymphoproliferative syndrome (ALPS) with defects in apoptosis and therefore increased survival of autoreactive T-cells.

Endocrine autoimmune manifestations can occur among patients with APECED and IPEX, where infections are coupled with early onset adrenal or parathyroid disease or type 1 diabetes. APECED patients may present solely with candidiasis early in life, while autoimmune manifestations of the endocrine system may appear in later decades. On the other hand, for IPEX patients, around 75% have type 1 diabetes and 60% have autoimmune skin disease as early as infancy.

Hypomorphic genetic defects in the RAG1 or RAG2 (recombinase-activating gene) genes are also associated with an autoimmune presentation, along with a recently described phenotype of combined immunodeficiency (CID). Patients in this group have fewer infections than might be expected with this genetic defect, but late-onset autoimmune disease often occurs that may include destructive granulomatous vasculitis, myasthenia gravis, Guillen-Barre syndrome, and vitiligo. Ultimately, some of these patients require HSCT for resistant cases.

Patients with DiGeorge syndrome will infrequently present with autoimmune complications, including arthritis (2% in children, 8% in adults) and autoimmune cytopenias (4%). The autoimmune phenotype of Wiskott-Aldrich syndrome patients is quite variable (40%–72% prevalence), and has been shown in experimental models to be due to both defective tolerance of both T-cells and B-cells. Autoimmune manifestations include hemolytic anemia (~30%), arthritis, vasculitis, and inflammatory bowel disease. When associated with autoimmune manifestations, patients with Wiskott-Aldrich syndrome are more prone for poor long-term outcome and therefore qualify for early consideration of hematopoietic stem cell transplantation.

Currently, one of the great challenges in the treatment of autoimmune disorders is the occurrence of granulomatous conditions (mainly lung, but may occur in any mucosal surfaces, skin, and brain). These lesions can occur in a variety of PIs. In the lung, function can be severely impaired, and if associated with vasculitis may result in destruction of the surrounding tissues. Treatment with anti-inflammatory and immunosuppressive medications has shown success in reducing the impact of granulomatous conditions, including the use of rituximab and azathioprine (reference Chase et al., J Clin Immunol (2013) 33:30-39). In addition, autoimmune enteropathies can pose additional challenges to specialists and can contribute to low immunoglobulin (mainly IgG) levels and even loss of lymphocytes. In genetically susceptible individuals, triggers of enteropathy may include infections or dietary gluten or dairy. Severe diarrhea can start early in life in patients with SCID or IPEX; both of these immunodeficiencies are considered emergencies.