Primary and Acquired Immunodeficiency Disorders

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44 Primary and Acquired Immunodeficiency Disorders

Onajovwe. Fofah, Mary B. Fleck, Naimah. Campbell, Sheila Lenihan. Walsh, James. Oleske

A happy birth to 150 million infants born this year. May those who rule provide the simple gifts of peace: shelter,food and water, education and health.

But alas, though many millions are born, most are birthed alone with no one there but Mom to hear their cries, no host of angels calls their name and no kings of Orient travel to give them precious gifts.

Three million of these newborns die, as well as ten million children under five, most of their deaths could be avoided with a little food and water, simple gifts to give.

In our privileged lands, few children now have AIDS and die, but where most children live, five million will have AIDS and ten million more left to live alone, orphans with little hope of care.

We must not let another generation be lost nor any child suffer for lack of care. Health is a fundamental right, a wise gift the world and each one of us should make!

—J. Oleske

This chapter describes the critical role of palliative care services in improving the quality of life of the immunosuppressed child and his or her family. Primary immunodeficiencies are identified and distinguished from secondary immunodeficiencies, and the clinical features of each category are briefly described to give the reader an appreciation of the prevalence and impact of immunosuppression upon the growth and development of children.

The following pages explore the journey and reflect upon the impact of the devastation that the unanticipated AIDS epidemic brought upon the pediatric community. The need for supportive care to optimize quality of life for these children and their families is addressed and includes details of the initial development of investigative treatment trials, development of effective highly active antiretroviral therapy (HAART) and their role in prevention of perinatally acquired human immunodeficiency virus (HIV) infection, as well as cure of children with primary immunodeficiencies by immune reconstitution, or stem cells.

It is impossible to adequately describe the suffering of HIV-affected children and the impact upon those who care for them. Response to the lack of effective systems of service delivery has paved the way for the rebirth and evolution of palliative care in the pediatric community. Lessons learned about caring for families of children with HIV serve as a prototype to address the wide range of clinical, developmental medical, social, and political problems encountered by seriously ill children and their families, regardless of the nature of their illnesses. It is hoped that this chapter and others will further stimulate development of evidence-based protocols and practice guidelines to address important areas of palliative and end of life care, especially in underserved populations.

The initial eight cases of pediatric acquired immunodeficiency syndrome (AIDS) were reported in 1983 from the Pediatric Allergy-Immunology and Infectious Disease program in Newark, New Jersey, initially named the Children’s Hospital AIDS Program (CHAP).¹ When the children’s hospital closed in 1998, the Pediatric HIV/AIDS program was renamed the François-Xavier Bagnoud Children Center. One of the cases from this initial cohort best illustrates the recognition that these infants and children were part of the AIDS epidemic and not a sudden increase in a new form of primary severe combined immunodeficiency disorder (SCID).

Clinical Vignette

A 4-month-old girl presented with chronic diarrhea, leading to failure to thrive and wasting syndrome that was associated with recurrent and severe sino-pulmonary infections anemia, lymphopenia, generalized lymphadenopathy and thrombocytopenia. She was under the supervision of New Jersey’s Division of Youth and Family Service (DYFS) by a foster mother, because of abandonment by her chronically ill intravenous drug-using mother. Her initial immunologic laboratory evaluation showed a surprising hypergammaglobulinemia instead of the expected hypogammaglobulinemia, low total T cells and, as was typical for that era, low markers by immunoflorescent microscopy for helper T cells. A lung biopsy was done for chronic infiltrates. During the procedure there was little thymus tissue noted and a small piece was obtained for pathologic evaluation. The lung biopsy demonstrated severe lymphocytic iterstitial pneumonia (LIP) (Fig. 44-1) and the thymus biopsy was reported as showing chronic inflammation, calcified Hassall bodies with marked reduction in thymus lymphocytes. These changes were unexpected and consistent with a probable chronic perinatal infection (Fig. 44-2). Most importantly, she had an identical second-born twin sister who was and remains healthy (Fig. 44-3). Over time, HIV/AIDS was confirmed in the ill twin while her identical twin sister remained well and thriving with consistently negative HIV assays. Both are now 30 years old and the HIV-infected sibling has survived despite progression of her HIV to AIDS. Until specific HIV diagnostic studies became available, the care team, including one of the coauthors of this chapter (JO), diagnosed differentiated perinatal HIV from the assumed initial diagnosis of SCID, based on the unexpected results of lung and thymus tissue and the discordant clinical course of the twins.

Fig. 44-1 Chest x-ray showing changes of LIP.

Fig. 44-2 Thymus biopsy by H&E stain demonstrating changes consistent with chronic perinatal infection and not SCID.

Fig. 44-3 Picture of the two sisters at 18 months of age demonstrating the obvious physical discrepancy.

Epidemiology of Inherited and Acquired Immunodeficiency Syndromes in Childhood

Approximately 55,000 children, newborn to age 19, die in the United States annually, with nearly half of these deaths being infants, of which two thirds are neonates.² These infant mortalities are mostly due to prematurity as well as congenital and/or genetic abnormalities, both having primary or secondary immune dysfunction. Most of these secondary immune problems in the premature infant are related to innate immune dysfunction that include breaks in skin and mucus membrane integrity, nutritional deficiencies, exposure to nosocomial infectious agents and exposure to frequent procedures and broad-spectrum antibiotics. In older children, worldwide mortality has been decreasing, with most deaths attributed to chronic, life-limiting medical conditions. Primary and secondary immunodeficiencies in infants contribute considerably to infant mortality and pose a significant, but often not recognized, threat to the health and well-being of children in the United States.

Primary or inherited immunodeficiencies are almost always genetically determined, often confined to a few rare, familial, monogenic, recessive traits that impair the development or function of one or several leukocyte subsets and result in multiple, recurrent, opportunistic infections during infancy. With improved diagnostic capabilities and an increased understanding of human immune functions, these immunodeficiencies are proving to be more common than previously estimated and may affect a much larger population because of a broadening of the definition of primary immunodeficiencies (PID). Considerable expansion of the understanding of immunological changes is being demonstrated in multiple chronic diseases, as well as improved survival with more effective treatments (Table 44-1).³ The frequency of PID varies in different countries, with certain populations having higher frequency of some specific PID mutations.⁴ Progress in medical care has made it possible for many of these children with PID to survive to adulthood with symptoms and complications that may not be recognized by adult primary care providers.⁵

TABLE 44-1, A Classification of Primary Immune Disorders That Manifest in Neonates

Components of the immune disorder	Immune system	Inheritance / associated features
Predominant antibody defects	X-linked agammaglobulinemia Hyper IgM syndrome Transient hypogammaglobulinemia of infancy

XL/recurrent pyogenic infections

XL/neutropenia, thrombocytopenia, hemolytic anemia and opportunistic infections (mouth ulcers)

Variable/recurrent moderate bacterial infections/common

Predominant defects in cell-mediated immunity

Di-George anomaly

MHC class II deficiency

Neonatal HIV infection

De novo defect or AD/conotruncal malformation; hypoparathyroidism: cardiac outflow tract malformation; abnormal faces/common

AR/failure to thrive and protracted diarrhea/rare

Variable frequency-secondary cause of immunodeficiency

Combined antibody and cellular immunodeficiencies Wiskott-Aldrich Syndrome

XL/thrombocytopenia; small defective platelets, eczema; lymphoreticular malignancies; autoimmune disease

Bloody stools, draining ears/rare

Severe combined immunodeficiencies

X-linked SCID

Zap—70 deficiency

Adenosine deaminase deficiency

Omenn syndrome

Reticular dysgenesis

XL/symptoms may be similar to GVH disease in neonatal period (maculopapular rash, alopecia, lymphadenopthy)/rare

AR/very rare

AR/cartilage abnormalities/rare

AR (in most cases)/erythroderma, eosinophilia/rare

AR/lethal shortly after birth/extremely rare

Defects of phagocytic function

Chronic granulomatous disease of childhood (CDG)

Schwachman syndrome

Leukocyte adhesion defect

Both XL/AR defective NADPH intravacuole killing of catalase-negative organisms

AR/anemia, thrombocytopenia, pancreatic insufficiency, hypogammaglobulinemia

AR/delayed umbilical cord detachment, leukocytosis, recurrent infections/very rare

Complement deficiencies C5, C6, C7, C8a, C8b, C9 deficiency AR/neisserial infections, SLE/very rare or rare Auto Inflammatory disorders Neonatal onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA) AD/Neonatal onset rash, chronic meningitis, and arthropathy with fever and inflammation in response to IL-1R antagonist (Anakinra)/very rare

XL—X-linked

AD—Autosomal dominant

AR—Autosomal recessive

MHC—major histocompatibility complex

Notarangelo L et al. International Union of Immunological Societies Expert Committee on Primary Immunodeficiencies: Primary immunodeficiencies: 2009 update. J Allergy Clin Immunol 2009: 124:1162 –1178.

An example of the challenges of caring for a child with PID can be demonstrated by a case of a child with Wiskott-Aldridge syndrome who was cared for by our immunology service from the age of 6 through his death at 24 years. He was one of the initial children enrolled in the Circle of Life Children Centers (COLCC), a palliative and end-of-life care program, established in 2002.

Clinical Vignette

When first seen at age 6 in 1986, the boy had a history of recurrent bacterial sino-pulmonary infections, chronic mild thrombocytopenia, and a palpable spleen. He was brought by his mother, who was concerned about the risk of bleeding recently raised by his pediatrician, who thought the child would outgrow this problem. However, she was concerned that there might be more to his problem. Despite the abnormal history and examination, which revealed the appearance of mild eczema-like rash with scattered petechia and an enlarged spleen, he was a very active child who participated in several physical activities, including karate. The initial blood studies were consistent with Wiskott-Aldridge syndrome (WAS), which was later confirmed by finding the WASP gene mutation on the short arm of his X chromosome. From the outset, the mother wanted do whatever was in her son’s best interest. The treating immunologist tried to keep them both informed about latest recommendations in treating WAS. Over time, treatment included starting monthly intravenous gamma globulin replacement therapy, which was later changed to a clinical trial of bi-monthly subcutaneous preparation of gamma globulin to reduce the trauma and pain of finding an IV site. There were long visits to discuss the risk and benefits of splenectomy, cyclic use of rotating courses of antibiotics and always the give and take of negotiating limits of participation in contact sports or traumatic activities for a young adolescent who wanted to be normal, and who, with close medical care was, for the most part, feeling that he was normal. Although we were able to avoid splenectomy and keep him out of the hospital and attending high school, at age 15, he wanted to pursue the option of a cure by stem cell transplantation. After a prolonged search, a partial match was found and both patient and mother wanted to proceed, despite the known risk of failure and possible complications of transplantation, which increased with a less-than-identical match. After transplantation and over the following 5 years, he had only a limited reconstitution of immune function, but also developed all the complications that accompany this procedure, in their most extreme forms and degree. The worse was the need for more hospital stays than days spent at home. Despite his progressive downhill course, both the mother and the young man insisted on trying therapies regardless of significant known toxicities and risks, with little chance that they would help. There were times when he overcame setbacks with his inspiring courage and in so doing, was a positive example to other hospitalized but far less ill children. His love of life and mother drew the attention of government and civic leadership to focus on the plight of so little access and availability of pediatric palliative and end-of-life care, and helped start support for programs, such as COLCC, in addressing this need. His suffering and forbearance proved too great. Also so remarkable, at his funeral were the statements made by so many people of his impact on advancing the care and programs that will help many others to have the palliative and hospice care that was not allowed him.

Secondary or acquired immunodeficiencies are more common than primary disorders of immune function (Table 44-1, B). By far, the most common secondary immunodeficiency of this era is HIV/AIDS.⁶ Based on the original version of the PACTG 219 follow-up study from 1993 through 2000, Table 44-2 lists the most common diagnosis during that period when HAART therapy was not available.⁷ Unfortunately, children presenting with these diagnoses at birth through 4 years also experienced the highest mortality rate. In the older age groups, Pneumocystis jirovecii pneumonia (PCP) remained associated with a high mortality rate but lymphocytic interstitial pneumonia (LIP) was a marker for prolonged survival before HAART therapy.⁸ Sadly, during the early epidemic, despite a high morbidity and mortality rate, most attention was focused on treatment of opportunistic infections with little attention given to palliative and supportive care.

TABLE 44-1, B Classification of Immune Disorders Associated with or Secondary to Other Diseases

Disease	Immune disorder	Inheritance / associated features
Bloom syndrome	Reduced T-cell function and decreased IgM	AR/LBW, retarded growth, facial telangiectasia, sun-sensitive erythemia, increased susceptibility to malignancies, molar hypoplasia, bird-like face/ rare
Fanconi anemia	Decreased T lymphocyte and natural killer (NK) cell function, decreased IgA	AR/multiorgan defects, bone marrow failure, café au lait spots, limb defects, abnormal faces, hyperpigmentation
Xeroderma pigmentosa (XP with 7 subgroups A-G and a variant, XPV)	Decrease in CD4+ levels and function due to mutation of the DNA repair gene for ultraviolet (UV) induced damage.	AR/defect in nucleotide excision repair (NER) with mutations of important tumor suppressor genes (e.g., p53 or proto oncogenes) leading to a sixfold increase in metastatic malignant melanoma and squamous cell carcinoma as well as XP being six times more common in Japanese people
Cancers	Bone narrow suppression from tumor infiltration or ablation of marrow from therapy: drugs or radiation	An increasing number of cancers appear to be enhanced by specific genetic characteristics
Malnutrition	Both single nutrient/trace metal impact on specific immune function or generalized wasting	AR/acrodermatitis enteropathica (zinc deficiency)
Infections	Varies with organism and whether localized/systemic or acute/chronic	Chronic, multiorgan system viral infections predominate, penultimate example being HIV/AIDS
Prematurity	Greatest impact on innate host defenses	More profound when gestation <28 weeks because of sharp drop in maternal-to-fetus transfer of immunoglobulins
Chronic organ system diseases: diabetes or renal disease	Like infections, great variations with severity depending on single or multiple organ involvement, timing of onset	Depending on organ systems or specific cause of organ failure, there may be a genetic-linked immuno deficiency syndrome