A 3.5-year-old female patient suffered from repeated respiratory infections-pneumonia and obstructive bronchitis-with otherwise unremarkable physical development. Laboratory tests and a genetic analysis finally shed light on the matter.
Background: A three and a half year old female patient was referred to pediatric pneumology due to recurrent pneumonia as well as regular obstructive bronchitis since the age of six months. The obstructive bronchitis occurred about five times a year, but never required hospitalization and was easily treated with inhalation on an outpatient basis. Following a total of four episodes of bronchitis, the patient developed clinical symptoms of pneumonia, which was successfully treated on an outpatient basis with perorally administered antibiotics. In addition, a single diagnosis of otitis media acuta was made in the first year of life. Between episodes of respiratory symptomatology, the patient was physically well and without dyspnea. Development and growth were unremarkable and no chronic symptoms occurred. Family history revealed evidence of atopy in both parents, but otherwise there are no known congenital or severe diseases. The child’s mother suffers from Graves’ disease with hypothyroidism and recurrent sinusitis for several years.
History and Diagnosis: Physical examination and a chest radiograph revealed no abnormalities. Pulmonary function measurement was inconclusive due to moderate cooperation at this young age, but no evidence of chronic airway inflammation was found. The allergy screen was also unremarkable. Laboratory findings revealed moderate-severe hypogammaglobulinemia, but with adequate specific antibody response to protein- and polysaccharide-based vaccines. In contrast, measles- and varicella-specific IgG could not be detected despite two vaccinations. A T-cell defect as well as disorders of neutrophil or complement function could be excluded. A broad genetic screen for congenital immunodeficiencies (exome sequencing) revealed a previously unknown maternally inherited heterozygous variant in the PIK3CD gene, which, together with clinical symptoms, is compatible with activated PI3K delta syndrome (APDS) type 1.
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Initial diagnostics for suspected congenital immunodeficiency
In case of questions or uncertainty, contact should be made with an expert, e.g. at the Children’s Hospital Zurich as the only center for highly specialized medicine (HSM) in Switzerland in the field of special clarifications in children with primary (genetic) immunodeficiency. (Also available via tele-immunology: aerzte.immunologie@kispi.uzh.ch) |
Therapy and course: Treatment was in the form of intravenous IgG substitution since the age of four years. This quickly led to complete freedom from symptoms and has since been performed regularly every four weeks on an outpatient basis in a day clinic.
Comment by PD Dr. Dr. med. Johannes Trück: APDS is an autosomal-dominant inherited congenital immunodeficiency based on a dysfunction of the immune system. The symptoms can be very diverse, which makes the diagnosis difficult. Increased phosphoinositide 3-kinase (PI3K) activity over-transmits signals in cells, activating the immune system and causing immune cells to proliferate continuously. In addition, self-reactive cells can be produced in excess, which in turn can trigger autoimmune diseases. Aberrant proliferation can cause premature aging and death of immune cells. Due to the resulting immunodeficiency, patients with APDS often suffer from frequent infections in childhood, especially mucosa-associated infections such as otitis, sinusitis or bronchitis/pneumonia – as in the present case. However, the nature and intensity of the symptoms are highly variable and symptoms may well not appear until adulthood. Due to the clustered infections, organ damage, especially to the lungs in the form of bronchiectasis, can occur. In addition to immunodeficiency, some patients experience lymphoproliferation, such as swelling of the tonsils, adenoids, lymph nodes, or spleen. Immune dysregulation can manifest itself in the formation of autoantibodies and, consequently, in the development of autoimmune diseases that cause cytopenias, thyroiditis or arthritides. Furthermore, some patients develop chronic inflammatory bowel disease. In addition, APDS patients are at increased risk for developing lymphoma.
PD Dr. Dr. med. Johannes Trück
Senior physician pediatric immunology and research group leader
University Children’s Hospital Zurich and Research Center for the Child (FZK), University of Zurich (UZH), Zurich, Switzerland.
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“ELVIS” as an acronym for a pathological susceptibility to infection. E – Pathogens: infections with opportunistic pathogens, e.g. Pneumocystis jirovecii pneumonia, recurrent severe infections with common germs. L – Localization: infections in unusual locations, e.g., brain / liver abscess, or recurrent severe polytopic infections. V – Course: protracted course of infections; inadequate response to antibiotics; unusual course of infections with “common” pathogens (e.g., herpes viruses). I – Intensity: infections with a high degree of severity, e.g. sepsis, meningitis or pleuropneumonia. S – Total: common (minor) infections, e.g. upper respiratory tract infections, obstructive bronchitis, otitis media (a “normal” number of infections is difficult to define and highly age-dependent). Source: https://www.awmf.org/leitlinien/detail/ll/112-001.html |
This text was produced with the financial support of Takeda Pharma AG.
C-ANPROM/CH/CUVI/0012 06/2021
Article online since 07.09.2021
