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Primary and Acquired Immunodeficiency Disorders
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). 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.
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. 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 ). The frequency of PID varies in different countries, with certain populations having higher frequency of some specific PID mutations. 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.
TABLE 44-1, A
Classification of Primary Immune Disorders That Manifest in Neonates
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.
| Components of the immune disorder | Immune system | Inheritance / associated features |
|---|---|---|
| Predominant antibody defects |
|
|
| Predominant defects in cell-mediated immunity |
|
|
| Combined antibody and cellular immunodeficiencies | Wiskott-Aldrich Syndrome |
|
| Severe combined immunodeficiencies |
|
|
| Defects of phagocytic function |
|
|
| 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
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. 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. 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. 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 |
TABLE 44-2
Most Common HIV Related Diagnoses
| Birth to 23 months | 2-4 years | 5-11 years | 12-21 years |
|---|---|---|---|
| Oral candidiasis (OC) | Lymphocytic interstitial pneumonia (LIP) | LIP | Pneumonia |
| Anemia | Anemia | Pneumonia | OC |
| Failure to thrive (FTT) | OC | OC | LIP |
| Pneumonia | Pneumonia | FTT | Varicella zoster |
| Pneumocystis jirovecii pneumonia (PCP) | FTT | Anemia | PCP |
Based on unpublished data from PACTG 219 Long-Term Follow-Up database.
Globally, an estimated 430,000 children younger than 15 were newly infected with HIV in 2008. The vast majority of these children (90%) acquired the virus via perinatal/mother-to-child transmission (MTCT). By the end of 2008, 2 million children were infected with HIV worldwide, with 280,000 children dying of the disease in that same year. In the United States, HIV has become the sixth-leading cause of death among 15-24 year-olds, and continues to disproportionately affect people of color. African Americans, who account for only 13% of the U.S. population, represent 51% of the estimated number of HIV/AIDS diagnoses made through 2007.
HIV is also transmitted via other routes, such as through blood transfusions as evidenced in the hemophilia population. Before the policies for screening HIV in blood supplies were instituted, many people were exposed to the virus through intravenous transfusions of blood or blood products. People with hemophilia routinely need certain blood-clotting components, and receive them through frequent blood transfusions. From 1978 through 1985, many hemophiliacs were inadvertently put at extremely high risk for acquiring HIV through the public blood supply. Hemophiliacs now represent 1% of all people with AIDS in the United States.
The final group of children who acquire HIV are victims of sexual abuse. A small percentage of children (<1%) acquire HIV through sexual abuse by an infected adult male, usually a relative or close friend of the family. Because sexual abuse of children is likely to be under-recognized and under-reported, sexually abused children are not routinely screened for HIV infection, and sexually abused children infected with HIV who have not progressed to AIDS are not reported in many states, the full extent of sexual transmission of HIV among children is not known. It is important to also note that among adolescents ages 15 to 19, the major cause of HIV infection is through high-risk sexual activity.
Symptoms, Distress, and Quality of Life in Children and Adolescents with Immunodeficiency Disorders
Clinical manifestations of HIV in children include recurrent bacterial infections; recurrent and intercurrent opportunistic infections; neuro-psychiatric manifestations; gastrointestinal problems, such as diarrhea and malnutrition; weight loss; respiratory problems, such as pneumonia and bronchiectasis; and skin manifestations, such as herpes simplex, seborrhoeic eczema, and molluscum contagiosum. Other problems include lymphadenopathy, hepatosplenomegaly, oral candidiasis, failure to thrive, wasting syndromes, parotitis, malabsorption, and developmental delays and/or loss of developmental milestones. Acute, chronic, and recurrent pain may be related to the disease, to progression, and/or to medications, treatments, and procedures.
Children and adolescents with HIV experience more subjective distress than their uninfected peers, including dysphoria, hopelessness, preoccupation with their illness, and poor body image related to their physical appearance affected by wasting and dermatologic conditions. “Attempting to cope with HIV-positive serostatus may trigger social withdrawal, depression, loneliness, anger, confusion, fear, numbness, and guilt.” Children in particular may believe that they did something terrible to deserve HIV, resulting in the development of guilt. “Non-infected siblings are also affected by HIV. Sibling relationships may be damaged by a fear of contagion or feelings of resentment towards the ill child. Because of these multiple difficulties, siblings of infected children also often experience problems in school.”
In addition to increased distress, adolescents with HIV often experience greater physical pain, which is a frequent accompaniment to AIDS. Almost 60% of children with HIV experience pain, which may negatively affect their quality of life and sleep patterns. Chest pain, headache, oral cavity pain, abdominal pain, and peripheral neuropathy are commonly reported. As in other chronic illnesses, pain needs to be understood within a developmental context so that preventive and therapeutic intervention strategies can be developed to reduce children's distress.
Treatment
Treatments for HIV-1 disease complications that improve quality of life include HAART, prevention of bacterial infections, and the provision of prophylaxis and treatment of opportunistic infections such as Pneumocystis jirovecii pneumonia(PCP) , atypical mycobacteria infection (MAC), cryptococcal meningitis, toxoplasmosis, cytomegalovirus, and herpes simplex virus. Good nutrition is a critical component in health maintenance and quality of life. These measures, in addition to good supportive care, have slowed the progression of HIV infection. As a result, many more HIV-infected children are now living longer, well into their teens. Palliative care needs to be integrated with cure-directed therapy and should be available from diagnosis through the entire course of the disease.
Although HAART dramatically changed the outcome for many HIV-infected children in developed countries, problems with adherence to or tolerance of therapy, and the increasing viral resistance rate to multiple antiretroviral drugs suggest that the need for palliative, respite, and hospice care for HIV-infected children will increase. The picture in the resource-poor areas of the world is very different. More than 90% of HIV-infected children who reside in these countries lack access to many therapies such as HAART, PCP, or MAC prophylaxis, that would prevent disease progression and are considered part of the continuum of palliative care.
HIV disease-related pain
HIV disease-related pain results from both infectious and noninfectious processes in various organ systems that can be acute or chronic. Causes of oropharyngeal pain include candidiasis, dental problems, periodontitis, gingivitis, aphthous ulcers, and herpetic stomatitis. Esophageal pain, or dysphagia, can result from esophageal candidiasis, CMV, or herpetic ulcerative esophagitis. A rare cause of dysphagia may be lymphoma. Common causes of abdominal pain include pancreatitis, hepatitis, cholengitis, MAC enteritis or colitis, CMV colitis, and inflammatory or infectious colitis. Chronic diarrhea, although not classically considered a pain syndrome, is common in HIV disease and is usually associated with abdominal discomfort, including cramping and spasms.
The oropharyngeal and gastrointestinal pain syndromes frequently result in poor oral intake and reduced absorption of nutrients, which lead to malnutrition and failure to thrive, and progresses to wasting syndrome. Even in the early stages of HIV disease, the recurrent difficulty with oral intake from various causes may have a significant impact on quality of life. The wasting syndrome is commonly associated with cachexia, fatigue, depression, musculoskeletal pain, abdominal pain, and neuropathy secondary to nutritional deficiencies. The chronic pain and suffering experienced by HIV-infected children with wasting syndrome is one of the most challenging pain syndromes to effectively treat and relieve.
Neurologic and neuromuscular pain syndromes are relatively common in HIV-infected children. These include hypertonicity; spasticity; encephalitis, including herpes and toxoplasmosis; meningitis, such as Cryptococcus neoformans ; primary CNS lymphoma; Guillain-Barre syndrome; and myopathy. Peripheral neuropathies, or the possibility that the neuropathy might be a drug side effect such as to an antiretroviral, should be remembered. Skin and soft tissue complications of HIV, which are associated with both acute and chronic pain and discomfort, include herpes simplex, shingles, and other bacterial or fungal infections, as well as adenitis caused by bacterial or mycobacterial agents. Malignancies such as leukemia, lymphoma, and leimyosarcoma, which seem to be more frequent in HIV-infected children, have cancer-associated pain syndromes in addition to the HIV-associated symptoms.
HIV treatment-related pain
Some chronic pain experienced by HIV-infected children is related to the side effects and toxicities of the multiple medications used, especially antiretroviral medications. A detailed description of the specific side effects of each antiretroviral is available in published pediatric treatment guidelines. Many of the antiretroviral medications cause abdominal discomfort, nausea, and diarrhea. This is especially true for the protease inhibitors as a class, but is also seen with nucleoside analogues, such as didanosine and zidovudine. Other painful side effects associated with antiretroviral drugs include headache, pancreatitis, and neuropathy. Patients often need to continue the medications causing these symptoms and are asked to live with these side effects or risk development of drug resistance and disease progression. In addition to the pain associated with antiretroviral therapy, the stress of adherence to these complex regimens has its own adverse impact on quality of life.
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