A 26-month-old girl was admitted to inpatient clinics with the complaints of recurrent oral Candidiasis, lower respiratory tract infections, and diarrhea. Candidiasis recurred whenever antifungal treatment was interrupted since the newborn period. She had bronchiolitis, pneumonia, and otitis media recurring 4-5 times a year, and these infections had started in the first month of life. She had a severe varicella infection when she was 5 months old. She had mild mental and motor developmental delay. She was the second child of third-degree consanguineous healthy parents. Her elder six-month-old brother died due to pneumonia. No further information on the nature of his infection could be obtained, and it was learned that no evaluation was carried out for him.
She had failure to thrive (height and weight under the third percentile), oral Candidiasis, and bronchitis at admission. Complete blood count and biochemistry were normal. C-reactive protein was 1.7 mg/dL (normal: <0.3 mg/dL), and erythrocyte sedimentation rate was 10 mm/hour (normal: <20 mm/hour). Chest X-ray revealed bilateral microcalcifications and chronic lung disease findings. There were bilateral multiple parenchymal nodules, the biggest one being 5 mm, in high-resolution CT (Figure 1). An 8 mm calcific nodular lesion of the liver was reported and interpreted as a granuloma in the abdominal US.
 Candida albicans was isolated from oral mucosa swab. Blood Aspergillus antigen was negative. Rhinovirus antigen was detected in a nasal swab. CMV and EBV DNA (1966 IU/ml and 7600 IU/ml, resp., by PCR) were present in blood and successfully treated with ganciclovir, significantly lowering the titers. However, these tended to rise again with pneumonia or gastroenteritis attacks or upon temporary withdrawal of the drug, suggesting chronicity. As oral fluconazole was not effective for Candidiasis, parenteral caspofungin was initiated with good response. E. coli grew in urine culture which was responsive to proper antibacterial medication. Tuberculin skin test was negative; interferon-gamma release assay (IGRA) was positive.
Mucopurulent secretions and mucous plaques on airways with normal anatomical structure were observed by bronchoscopy. Bronchoalveolar lavage fluid had benign cytology, and there was no evidence of bacteria, fungi, parasites, or mycobacteria. Repeated IGRA was found to be negative, and isoniazid (INH) prophylaxis was preferred instead of multidrug tuberculosis treatment. It was discontinued due to increased liver enzymes after the second month.
Investigations for persistent diarrhea showed negative results for viruses, parasites, and bacteria. Recurrent vomiting was also a problem in the patient. Upper gastrointestinal barium scan and pH monitorization did not show gastrointestinal reflux. The endoscopic evaluation revealed inflammatory findings in esophagus and bulbus with a loose lower esophageal sphincter. There were no candidal plaques, probably because she was under antifungal treatment at the time of examination. Pathological studies showed eosinophilic esophagitis and fibrosis.
Vaccine responses to Hepatitis B, Rubella, and Mumps were positive. Autoantibodies (antinuclear antibody, anti-gliadin antibodies, anti-thyroid peroxidase, and anti-thyroglobulin antibodies) and direct Coombs tests were negative, and thyroid hormone levels were normal.
First line immunological workup revealed hypergammaglobulinemia with normal complement and IgE levels. Percentages and numbers of lymphocyte subgroups were normal compared to age-related healthy controls (Table 1). The quantitative determination of oxidative burst, the foxp3 expression on CD4+CD25+ T cells, and in vitro T-cell proliferation response to mitogens were normal.
She had chronic recurring infections with various pathogens including fungi, viruses, and bacteria. She had hypergammaglobulinemia, persistent oral Candidiasis, persistent granulomas, and nodules in the liver and the lungs. She was unresponsive to oral treatment and required parenteral treatments with frequent, over one-week hospitalizations warranting extensive workout for PID. Type and course of the infections with substantial organ damage suggested the presence of a severe combined immune deficiency, Mendelian susceptibility to mycobacterial diseases (MSMD), or CMC as preliminary diagnoses.