May 1, 2006
By: Mark Goldblatt, MD, William T. Basco, Jr, F.M. Schaffer, MD
Rochelle Hirschhorn, MD, professor of medicine, cell biology, and pediatrics at NYU Medical Center, New York, N.Y., provided invaluable assistance in determinations of adenosine deaminase (ADA) enzyme activity in specimens collected from the patient.
DR. GOLDBLATT is an attending physician in internal medicine and pediatrics at the Northern Navajo Medical Center, Shiprock, N.M.
DR. BASCO and DR. SCHAFFER are associate professors of pediatrics at The Medical University of South Carolina, Charleston.
DR. SIBERRY is an assistant professor of pediatrics in the divisions of general pediatric and adolescent medicine and pediatric infectious diseases at Johns Hopkins Hospital, Baltimore.
The authors and section editor have nothing to disclose in regard to affiliations with, or financial interests in, any organization that may have an interest in any part of this article.
On a Friday evening, in a tertiary care hospital, a pager that’s been hotter than a Saharan mid-afternoon goes off, again. Seems like it’s the hundredth call today. And, once again, it’s all yours! You head to the nearest telephone. On the other end is a physician you know from a community hospital some 150 miles from your facility. She’s requesting transfer of a 7-month-old boy who has been hospitalized for the past six weeks for failure to thrive, recurrent wheezing, and bilateral infiltrates refractory to antibiotics. You happily accept the patient and quickly relay the information you have to the on-call resident.
Despite the busy evening, there’s time for your creative juices to begin to swirl as you await the transfer. A differential gathers. Respiration, you consider, can consume as much as two thirds of metabolic demand, resulting in failure to thrive. Will the baby’s lungs be the key to a diagnosis? But what about the wheezing? As an “old doc” once told you, there are only a few general causes of wheezing: reactive airway disease (asthma, allergies, mastocytosis), infection (respiratory syncytial virus, human metapneumovirus), a foreign body, a structural defect (slings, rings, bronchiectasis), a genetic disorder (including cystic fibrosis), and heart failure.
Back to the business of fact-gathering
The patient arrives at your facility and the team begins its evaluation to gather a detailed understanding of his condition. His mother has accompanied him; she reports that he is the product of a full-term pregnancy that was complicated only by a case of genital warts. Delivery was vaginal. Birth weight was 3.3 kg.
The boy was hospitalized at 1 month of age for fever. A workup for sepsis was negative. He was seen by his pediatrician at 3 months of age for bronchiolitis. She reports that he had intermittent episodes of wheezing over following months.
During his sixth month, he was seen in the emergency department of the referring hospital three times for cough, low-grade fever, rhinorrhea, wheezing, thrush, and poor oral intake. The first two times, he was sent home on an antibiotic and an inhaled bronchodilator. At the third visit, he was admitted; over the course of one or two days before that hospitalization, the patient had a persistent fever (to 102° F), poor oral intake, increasing fatigue, and difficulty breathing—all despite nebulizer treatments, antipyretics, and multiple attempts to feed him. The chart from that admission notes desaturations in the 80% to 89% range while breathing room air; fever; bilateral infiltrates on a chest radiograph; and thrush.
The course of illness at that hospital was marked by a range of therapeutics: three weeks of parenteral ceftriaxone; 10 days of amoxicillin-clavulanate; two courses of azithromycin; courses of fluconazole and econazole nitrate; a short course of parenteral nutrition; a scheduled multivitamin; and scheduled nebulized budesonide (Pulmicort), albuterol, and ipratropium bromide (Atrovent).
Despite your knowledgeable colleague’s treatments and extensive work-up, the baby continues to have thrush, wheezing, and respiratory difficulties and hasn’t gained weight. You review the initial history that was taken upon presentation at the referring hospital when the baby was 5 months old. The notes describe a male full-term, African-American infant with a maternal complaint that the baby has had a life-long history of “cold”-like symptoms. As already reported by the mother and documented in the hospital record, the patient had been seen in the ED twice in the month before the 5-month-old admission, for intermittent “rattling cough,” wheezing, low-grade fever (to 101°F) and poor oral intake without nausea, vomiting, or diarrhea. At each ED visit, he was sent home with a prescription for a course of oral antibiotic, and his mother was encouraged to treat him with the home nebulizer.
Five days before the baby was admitted at 5 months of age, he was seen by his pediatrician, who prescribed a course of ocular antibiotic drops for bilateral conjunctivitis, which, his mother tells you, resolved with treatment.
You obtain more history. The patient lives with his mother, father, and an older sister; there are no pets. Immunizations are up to date. He does not attend day care. Domestic water supply is from a municipal source. He has reached the developmental milestones of only a 4-month-old.
The family history is significant only for systemic lupus erythematosus in his maternal grandmother. All other family members are in good health. The parents report no unusual or potentially hazardous occupational exposures.
The physical exam in your ED today revealed an ill-appearing infant with a rectal temperature of 102.3°F; respiratory rate, 44/min; heart rate, 200/min; and oxygen saturation, 97% breathing room air, with frequent desaturations into the 80% to 89% range. Weight is 5.9 kg (below the fifth percentile). Examination of the head, ears, eyes, nose, and throat (HEENT) was significant for bilaterally bulging, erythematous, and thickened tympanic membranes and purulent effusions, as well as white lacey plaques on the tongue and buccal mucosa without tonsillar hypertrophy.
The neck showed no evidence of lymphadenopathy, thyromegaly, or masses. The cardiovascular exam revealed regular rhythm with tachycardia but no murmurs, rubs, or gallops. Diffuse inspiratory rales and rhonchi, diminished bibasilar breath sounds, and a prolonged expiratory phase were noted on the pulmonary exam. The remainder of the physical exam was unremarkable.
A few moments away to think: What’s the connection?
Later, sitting in your office, you begin to formulate a differential diagnosis that accounts for the failure to thrive, developmental delay, thrush, and refractory pulmonary process. Your focus is still on the lungs, and includes recurrent infections, caused by acquired pathogens or as a consequence of a congenital abnormality. Your explanations include hospital-acquired pneumonia, structural abnormalities such as rings and slings, cystic fibrosis, and reactive airway disease, among others. You’ve decided to extend your differential, however, to include inborn errors of metabolism; endocrine, immune, and autoimmune abnormalities; malignancy; and, although less likely, cardiac diseases and abnormalities. In fact, the differential seems limitless as you build it!
Fortunately—for you—the night passes quickly and you find yourself on rounds early Saturday morning.
The next morning, you examine the baby; he is afebrile. Heart rate is 140/min; respiratory rate, 27/min; and oxygen saturation, 100% on room air. He is visibly small—weight, height, and head circumference would be at the 50th percentile for a 2.5-month-old (but are proportional)—yet remains active and alert. Despite a careful exam, you cannot palpate any peripheral lymph nodes, and no tonsillar tissue is visible.
The abdomen is soft and non-tender, with active bowel sounds and without hepatomegaly or splenomegaly. The neurologic exam is remarkable for a diminished response to noise. Tone is only that of a 4-month-old child, and he still cannot sit unassisted.
Your pulmonary exam reveals intermittent scattered wheezes, rhonchi, and bilateral crackles that you can best describe as “Velcro-like.” Examination of the skin reveals multiple hypopigmented patches on the arms, chest, and shoulders.
You consider that, despite six weeks of therapy, your young patient continues to have persistent pulmonary findings, failure to thrive, and thrush. Is it possible that these ailments are iatrogenic? One complicated scenario comes to mind: What if this baby aspirated a small object, such as a sunflower seed, given to him by his older sibling? That foreign body resulted in shifting infiltrates, wheezing, rhonchi, and a post-obstructive process; in the hospital, he contracted an RSV infection from another child, or a hospital-acquired pneumonia. The thrush is a result of inhaled corticosteroids or prolonged courses of antibiotics, or both, and the failure to thrive is caused by respiratory distress or antibiotic-induced diarrhea. It’s time to test these possibilities, and others.
You, and one of the residents, quickly review the referring hospital’s work-up, including an extensive battery of laboratory tests: a basic metabolic profile, multiple blood and urine cultures, complete blood count, chest and abdominal radiographs, renal ultrasonography, thyroid function, sweat chloride assay for cystic fibrosis, ELISA for human immunodeficiency virus (HIV) infection, total hemolytic complement study (CH50), liver function, immunoglobulins, and the acyl-carnitine level. You note several important findings: persistent bilateral interstitial infiltrates on chest radiographs; a negative sweat chloride test for cystic fibrosis; a negative HIV ELISA study; normal renal function; a recent elevation of transaminases in the face of low albumin; low levels of complement, immunoglobulins, and acyl-carnitine; negative urine and blood cultures; mild anemia and leukopenia; and a normal level of thyroid-stimulating hormone.
You sift through all this information, struggling with how to make sense of the earlier test results and what you’ve learned from your history and physical exam. What do you know? Is it possible to make the definitive diagnosis with what you know already?
So whadda ya know?
You know that your patient is a 7-month-old male who began to fail to thrive two months ago despite a hospital stay that included supplemental and parenteral nutrition. He has recurrent infiltrates on a chest radiograph and persistent thrush. He has had low levels of immunoglobulins, complement, and acyl-carnitine; leukopenia; and anemia. At the moment, your differential diagnosis is broad and includes several categories of illness: congenital infection, immune deficiency, chronic lung disease, pulmonary malformation, metabolic and endocrine disorders, malignancy, autoimmune disease, and mechanical feeding difficulties.
Recurrent infections such as chronic gastroenteritis, recurrent thrush, and atypical severe infections (e.g., Pneumocystis carinii pneumonia), each in association with failure to thrive, are all histories consistent with a diagnosis of a combined immune deficiency (B and T cell) or a cellular (T cell) immune deficiency disorder.1 There is a relatively broad spectrum of immune deficiency states to consider in the differential; better-known disorders include severe combined immune deficiency (SCID), AIDS, DiGeorge anomaly, and the Wiskott-Aldrich syndrome (WAS).
With earlier test results in mind, you decide to order a basic metabolic panel, liver function tests, another chest radiograph, a CBC with a differential white count, and levels of ammonia, lactate, pyruvate, and serum amino acids. As the results slowly arrive, you note that serum electrolytes and renal function are normal and elevated transaminase levels have returned to normal. Leukopenia and anemia persist, however: The white blood cell count is 3.8 X 103/μL (normal, 6 to 14 X 103/μL) without evidence of granulocytopenia.
Surprisingly, however, the absolute lymphocyte count is 114 X 103/μL, with peripheral eosinophilia. You quickly return to the lab reports from the other hospital and find that the lymphocyte count did not exceed 400 X 103/μL on any CBC during the hospital stay. You call the hospital and the baby’s pediatrician and request that all previous CBCs be sent to you. Upon reviewing additional ambulatory labs you realize the child has had lymphopenia since birth. Eureka!!!
You next order an immunology consult, an HIV polymerase chain reaction (PCR) study, and a test of serum immunoglobulin levels. The immunologist requests a repeat total hemolytic complement study, flow cytometric analysis, and in vitro lymphocyte mitogen stimulation studies. The consultant sends the child’s blood and his mother’s blood for evaluation of adenosine deaminase (ADA) activity.
Results begin to arrive the next day. Flow cytometric analysis demonstrates severe deficits in T, B and natural killer cell counts. ADA activity is abnormally low in the patient and only approximately 50% of normal in his mother.
Because the patient has been severely lymphopenic (on the basis of routine CBCs) throughout his life, with flow cytometry-documented low numbers of B and T lymphocytes and natural killer cells, his test results are most consistent with SCID. The diagnosis now reveals itself: Your patient has ADA-deficient SCID, corroborated by the results of in vitro lymphocyte stimulation studies—namely, minimal T cell responsiveness to the T cell mitogens of phytohemagglutinin and concanavalin A and minimal response to T cell-dependent B cell pokeweed mitogen.
You consider that the absence of lymphoid tissue on physical examination is noteworthy. This finding is characteristic of SCID and of X-linked agammaglobulinemia and severe cellular immune deficiency disorders.2 Because this patient does not show evidence of hypocalcemia and characteristic facies and cardiac anomalies, the diagnosis of DiGeorge anomaly is unlikely. And without a history or evidence of ecchymoses, spontaneous hemorrhage, thrombocytopenia, and small platelets, Wiskott-Aldrich syndrome is also unlikely. Last, HIV ELISA and PCR studies were negative, which, for all purposes, rules out AIDS as the cause of the immune deficiency state.
Shortly after the diagnosis is made, histocompatibility testing is performed on blood specimens from all immediate family members to determine the optimal potential bone marrow transplant donor. Transfer to a pediatric center that specializes in bone marrow transplantation for SCID is arranged.
Before transfer is possible, the baby develops rotavirus enteritis. In an attempt to lower the intestinal viral load, he is treated with enteral gamma globulin. Once that infection resolves, he undergoes bone marrow transplantation with marrow donated by his mother, a haplo-identical match.
The transplant fails to engraft. His hospital course is complicated by recurrent rotavirus infection, and he develops hepatoblastoma. During treatment for the malignancy, he is started on the remaining therapeutic option for his immune deficiency disorder: weekly injection of polyethylene glycol-conjugated bovine ADA (PEG-ADA), to which his response is good, with improved T cell function. The following winter, he weathers a bout of influenza.
The forms and presentations of severe combined immune deficiency
SCID is one of more than 90 different primary immune deficiency states that have been described (“primary” meaning a heritable, not acquired, disorder). This class comprises heterogeneous rare genetic disorders that present in childhood and are generally fatal without treatment. It is estimated that approximately one in 100,000 live births in the US are affected by a primary immune deficiency disorder. All forms of SCID are characterized by absolute lymphopenia, which involves T, and often B, cells. Although B cell numbers may be preserved in some forms of SCID, they are nonfunctional in vivo. In some forms of SCID, a normal level of natural killer cell function is maintained.3
The presentation during the first year of life is predictable, particularly as passive immunity from transplacentally acquired maternal IgG wanes.4 Failure to thrive and recurrent infections—including thrush, chronic gastroenteritis, chronic lung disease, and atypical infections—should raise the question of whether a child has a combined immune deficiency with B and T cell deficits or a cellular immune deficiency with a T cell deficit solely.3
A child who has a T cell deficiency generally manifests clinical findings at 4 or 5 months of age. He may lack lymphoid tissue, and a thymic shadow may be absent on radiography. The deficiency results in recurrent infections with viral, fungal, mycobacterial, and parasitic pathogens. The child fails to develop immunity after routine childhood vaccinations—much like this patient—and a live vaccine, such as bacille Calmette-Guérin, can be fatal.3
Malignancy is common in SCID because the patient lacks tumor suppressor activity because of deficits of natural killer and T cells. Graft-versus-host disease (GVHD) may occur by various means: transplacental passage of competent maternal T cells, secondary to non-irradiated blood product transfusion (containing competent T cells), and after bone marrow transplantation. Early signs and symptoms are eosinophilia, rash, gastrointestinal symptoms, and elevated levels of liver transaminases.3
Pure B cell deficiencies are generally characterized by recurrent infection with encapsulated bacteria, which can result in recurrent sinopulmonary infection, lymphadenitis, meningitis, and osteomyelitis. Symptoms often do not develop until 7 to 9 months of age, when levels of transplacentally acquired maternal antibodies wane.1,4 Growth impairment is variable. Affected persons are at increased risk of autoimmune disorders; in some, lymphoid hyperplasia may be evident as hepatosplenomegaly.
Eosinophilia is seen in some SCID patients and in those who have one of the other primary immune deficiencies (e.g., Wiskott-Aldrich syndrome, hyper-IgE syndrome).3 Primary immune deficiency thereby adds an additional “P” to the mnemonic NAACP for eosinophilia: neoplasia, Addison disease, allergies and asthma, collagen vascular disease, cholesterol emboli, parasites, and primary immune deficiency.
The presence of eosinophilia in this patient may have been consistent with a parasitic infection, a developing neoplastic state, early developing GVHD, or Omenn syndrome. Highly unlikely here is Omenn syndrome: Reported cases are characterized by a recombinase-activating gene (RAG) deficiency, which results in SCID with minimal T and B cells but usually normal numbers of natural killer cells because RAG genes are not involved in natural killer cell ontogeny.3 Our patient, on the other hand, demonstrated a minimal presence of natural killer cells. In fact, this child was believed to have early GVHD—most likely, from transplacentally acquired competent maternal T cells; he had no prior transfusion of blood products or earlier evidence of a parasitic or neoplastic disorder. In fact, treatment to minimize GVHD was instituted before bone marrow transplantation.
An X-linked form and several autosomal-recessive forms of SCID have been well characterized. Although X-linked SCID accounts for nearly half of cases, the ADA-deficient form is one of the more common autosomal recessive forms. Absence of ADA leads to a buildup of intracellular lymphotoxic metabolic products.5 Providing a normal, functioning ADA gene through bone marrow transplantation or providing active, functioning enzyme with PEG-ADA allows for appropriate catabolism of these toxic metabolites.3
Because of the variable presentation of SCID and other primary immune deficiencies, they are often a challenge to the diagnostician: Subtle onset can delay diagnosis and treatment, thereby raising the risk and severity of morbidity and the risk of death. To avoid such consequences, always pay close attention to any lymphopenia, and always consider an immune deficiency in the presence of a combined clinical presentation, such as recurrent thrush, persistent sinopulmonary disease, unexplained rash, or recurrent diarrhea coupled with failure to thrive. Remember that connection, and you may very well “skid” into the right diagnosis!
1. Schaffer FM, Ballow M: Immunodeficiency: Office work-up. J Resp Dis 1995;16:523
2. Ballow M, Schaffer FM: Molecular genetics of immunoglobulin genes and the generation of antibody diversity, in Levsin AL, Patterson Y (eds): Molecular and Cellular Immunology of the Allergic and Immune Response. New York, Marcel Dekker, 1994, pp 3-40
3. Buckly RH: Primary cellular immunodeficiencies. J Allergy Clin Immunol 2002;109:747
4. Schaffer FM, Newton JA: Intravenous gamma globulin administration to common variable immunodeficient women during pregnancy. Case report and review of the literature. J Perinatol 1994;14:114
5. Hirschlhorn R: Overview of biochemical abnormalities and molecular genetics of adenosine deaminase deficiency. Pediatr Res 1993;33(1suppl):S35