A 3-year-old girl, was referred to our pediatric pneumology department for recurrent respiratory infection. The patient was the only child, born from unrelated parents of European ancestry. Family history was negative. The patient’s medical history was remarkable for the presence of eczema since the first month of age. From the second year of age, the patient presented recurrent respiratory infections, characterized by productive cough and fever, needing treatment with oral penicillin. Sixteen episodes occurred over only one year and in two occasions the patient was admitted to a local hospital with a diagnosis of pneumonia, and received intravenous antibiotic therapy. During one of the admissions mild lymphopenia and hypereosinophilia was noted (WBC count: 7200 cells/μL, total lymphocyte count was 1200 cells/μL, and eosinophil were 1500 cells/μL).

According to our first evaluation, the patient displayed a well appearance and her weight and height were on 25th percentile. A mild eczema was noticed at the root of the thighs and on the back. In chest auscultation, bilateral wheeze and crackles were present. Laboratory exams showed lymphopenia and hypereosinophilia (WBC: 4600 cells/μL, lymphocytes: 200 cells/μL, eosinophils: 1950 cells/μL, Hb: 13.6 g/dL, and platelets: 365,000/μL), with mild increase of inflammatory indexes (CRP: 9 mg/L, ESR: 31 mm/hr). Immunoglobulin count showed hypogammaglobulinemia with increased levels of IgE (IgG: 228 mg/dL, IgA: 21 mg/dL, IgM: 10 mg/dL, IgE: 170 IU/mL).

FormalPara Q1. What is the most likely diagnosis?
  1. A.

    Human immunodeficiency virus infection

  2. B.

    Active tuberculosis

  3. C.

    Primary immunodeficiency

  4. D.

    Churg-Strauss syndrome

  5. E.

    Cystic fibrosis

FormalPara Answer:

The correct answer is C.

Lymphopenia and hypereosinophilia can reflect either a primary or a secondary immunodeficiency. In HIV infection, high IgE and hypereosinophilia are related to the severity of the disease. Cutaneous infection with Candida albicans or scabies along with lymphopenia rises suspicion for Job syndrome. Acquired immunodeficiency syndrome (AIDS) is clinically characterized by hepatosplenomegaly, lymphadenopathy, and in contrast to congenital immunodeficiency, by the presence of hypergammaglobulinemia [1, 2]. Rarely, mycobacterial tuberculosis, especially in military forms, can present with peripheral eosinophilia, but the clinical response to penicillin made this hypothesis unlikely. Meanwhile, Mantoux and Quantiferon test were normal [3]. Although hypereosinophilia is a hallmark of Churg-Strauss syndrome, typical respiratory manifestations as treatment-refractory asthma and lymphopenia are not present [4]. Recurrent infections, lymphopenia and hypogammaglobulinemia, and presence of early onset eczema, are highly suggestive for a PID.

Total lymphocyte count was severely reduced (245/μL, with 212 T cells per μL). All lymphocyte subsets were deficient, with almost absent naïve T cells (recent thymic emigrants (RTE): CD45+RA+CD31+ = 19/μL). IgG anti-tetanus toxin and HBs antibody levels were protective.

FormalPara Q2. According to the above evidence, what is the most likely diagnosis?
  1. A.

    Wiskott-Aldrich syndrome

  2. B.

    Severe combined immune deficiency due to adenosine deaminase deficiency

  3. C.

    Late onset adenosine deaminase deficiency

  4. D.

    Hyper IgE syndrome due to DOCK8 mutation

  5. E.

    Hyper IgE syndrome due to STAT3 mutation

  6. F.

    Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

FormalPara Answer:

The correct answer is C.

Wiskott-Aldrich syndrome (WAS) and immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) usually occurs with untreatable diarrhea and eczema and affect boys. X-chromosome inactivation (i.e. lionization) can lead to a milder phenotype presenting in girls as well. Thrombocytopenia associated with small platelet volume is necessary for the diagnosis of WAS. IPEX is unlikely the diagnosis in this patient due to absence of autoimmune disorders and lymphopenia, although IPEX-like syndromes can present with abnormal lymphocyte count. Classical adenosine deaminase (ADA) deficiency present as profound lymphopenia (T−B−NK− severe combined immunodeficiency (SCID)) with severe infection and failure to thrive since early months of age [5]. Hyper-IgE syndrome due to STAT3 mutation is not associated with low lymphocyte count, as well as the characteristic facial features which are absent in this patient [6]. Late-onset ADA deficiency and hyper-IgE syndrome due to DOCK8 mutation are both consistent with the clinical picture of this patient: both present with progressive lymphopenia, elevated serum IgE, eosinophilia, recurrent pulmonary infection and precocious eczema. NK cell deficiency and only mildly elevated IgE levels, make late onset ADA deficiency, the most likely diagnosis.

FormalPara Q3. Which of the following options best describes common infections associated with ADA deficiency?
  1. A.

    Nontuberculous mycobacterial invasive infections

  2. B.

    Cutaneous abscess

  3. C.

    Recurrent osteomyelitis

  4. D.

    Bronchopneumonia and sinusitis

  5. E.

    Diarrhea

FormalPara Answer:

The correct answer is D.

Late-onset ADA deficiency manifests with recurrent infections beginning after 1 year of age. Typical infections include otitis, sinusitis, and upper respiratory infections. Moreover autoimmune disease and allergy are common. Neurologic impairment is far more prevalent in ADA deficiency compared with other primary immunodeficiencies, and include cognitive deficits, behavioral problems and sensorineural hearing loss [7]. Chest X-ray of this patient highlighted increased interstitial marking while CT excluded bronchiectasis (Fig. 30.1).

Fig. 30.1
figure 1

X-ray of the chest showing interstitiopulmonary reinforcement due to recurrent pulmonary infection (a) and CT-scan of the chest showing in transverse section an interstitiopulmonary reinforcement due to recurrent pulmonary infection (b) in a 3-year-old girl with recurrent respiratory infection

Full size image
FormalPara Q4. What is the most appropriate test to confirm the diagnosis of ADA deficiency?
  1. A.

    Lymphocyte subset panel

  2. B.

    Molecular gene testing

  3. C.

    ADA catalytic activity and toxic adenosine metabolites

  4. D.

    Lymphocyte proliferation assay

  5. E.

    Bone marrow aspirate and biopsy

FormalPara Answer:

The correct answer is C.

First line diagnostic test is based on assessment of ADA enzyme catalytic activity in hemolysates, extracts of dried blood spots with EDTA or heparin. If ADA activity is below 1% of reference value, the diagnosis is likely. False negative results can be due to recent erythrocyte transfusion. Lack of the enzyme adenosine deaminase results in an accumulation of deoxyadenosine, a toxic metabolite that is supportive to the diagnosis. In the described patient, ADA activity was below 1% and toxic metabolites were elevated. Genetic analysis showed c.385G > A p.Val129Met mutation that is reported to be associated to delayed onset ADA deficiency [8,9,10]. Unfortunately, our patient is the only child of her family and an HLA-identical sibling was lacking.

FormalPara Q5. What is the treatment option of choice in this patient?
  1. A.

    Bone marrow/stem cell transplantation from an HLA-haploidentical donor

  2. B.

    Enzyme replacement therapy

  3. C.

    Gene therapy

  4. D.

    Immunoglobulin

  5. E.

    Prophylaxis with co-trimoxazole and acyclovir

FormalPara Answer:

The correct answer is B.

In the absence of HLA-identical donor, e.g. from a sibling which entails the best treatment option, gene therapy is the recommended alternative [11]. However, there are some controversies in this regard. Enzyme replacement therapy was started to improve lymphocytes and hematopoietic stem cells counts (total lymphocytes: 1100/μL, 1007/μL, total T cells: 646/μL, CD4+ lymphocytes: 424/μL, CD8+ lymphocytes: 170/μL, total B cell count: 262/μL, natural killer cells: 56/μL, naïve T cells: 229/μL), which is a prerequisite to start a successful gene therapy. Moreover intravenous immunoglobulin replacement was started, together with co-trimoxazole, as antibiotic prophylaxis against Pneumocystis jirovecii, which is a typical infectious risk in patients with combined immunodeficiencies. Epstein-Barr virus, cytomegalovirus, hepatitis B and C infection, HSV-6 and HIV viral loads were negative and prophylaxis with acyclovir was started. Sputum culture was negative for acid fast bacilli.

FormalPara Q6. Which of the following symptoms shows more improvement through enzyme replacement therapy?
  1. A.

    Cytopenia

  2. B.

    Neurologic impairment

  3. C.

    Lymphopenia

  4. D.

    Autoimmunity

  5. E.

    Lymphoproliferative disorder

FormalPara Answer:

The correct answer is C.

Enzyme replacement therapy prevents accumulation of toxic metabolites and most individuals treated with PEGylated ADA (PEG-ADA) restore partial immune function that is sufficient to prevent opportunistic infections and other clinical manifestations of SCID. Other manifestations of ADA deficiency including autoimmune disorders and neurological impairments are not amenable to this treatment [7, 12]. Some authors suggest that the limitations of PEG-ADA efficacy is due to development of neutralizing antibodies that may lately emerge and hinder full function of the enzyme.

FormalPara Practical Points

  • The diagnosis of late-onset Adenosine deaminase deficiency (ADA) deficiency should be suspected in progressive lymphopenia associated with hypereosinophilia and moderately high IgE level

  • Late onset ADA deficiency present after first year of life, with mild recurrent infections, especially of the respiratory tract

  • Early-onset eczema is highly indicative of immunodeficiency

  • ADA catalytic activity is <1% of normal control, established diagnosis of ADA deficiency and allows to start a therapy.

  • Enzyme replacement therapy should be started and continued as a bridge to gene therapy or hematopoietic stem cell transplantation