A 4-month-old Hispanic female was admitted with nearly 2-month history of cough, posttussive emesis, gagging while feeding, and failure to thrive. She was born in the United States at 38 weeks estimated gestation via spontaneous vaginal delivery with uncomplicated pregnancy and delivery. The infant had mild left hydronephrosis identified by prenatal ultrasound that resolved spontaneously. After delivery, the infant was discharged home with mother in good health. Baby had two normal newborn screens. Family history was negative for immunodeficiency, tuberculosis, or lung disease. Upon developing cough at 2 months of age, she was evaluated as an outpatient by several providers. Due to chest radiograph findings of bilateral infiltrate, she was treated for presumed community-acquired pneumonia with oral antibiotics including 7 days of cefdinir and then 5 days of azithromycin, followed by 7 days of clindamycin without clinical or radiological improvement. At the time of admission for failure of outpatient therapy, physical examination revealed weight of 4.3 kg (<2%), length 58 cm (<5%), and head circumference 38.5 cm (<10%) with heart rate of 99 beats/min, respiratory rate of 40 breaths/min, and peripheral pulse oximetry of 98% on 5L high-flow nasal cannula supplementation. She was afebrile. Respiratory exam was positive for mild/moderate subcostal and intercostal retractions, nasal flaring, and decreased air entry bilaterally, but no wheezes nor crackles. She had evidence of systemic inflammatory response with elevated white blood cell count (24.5 K/CMM), elevated platelets (429 K/CMM), and inflammatory markers (CRP 5.1 mg/L, erythrocyte sedimentation rate 45 mm/hr.)
The Pediatric Pulmonology service was consulted and computed tomography scan of the chest showed large posterior bilateral perihilar opacities with sparing of pulmonary periphery and bases, with subcarinal lymphadenopathy (Figure 1). Purified protein derivative (PPD) skin test and T-SPOT . TB interferon-gamma release assay for tuberculosis were negative. Subsequently, bronchoscopy, bronchoalveolar lavage, and lung biopsy were performed. The patient's lung biopsy demonstrated "pleural and subpleural fibrosis and inflammation, mixed, focal neutrophilic aggregate, interstitial thickening with focal lymphocyte infiltration, and alveolar epithelial hyperplasia." The pathology report also indicated "a few clusters of histiocytes, but well-formed granulomas are not seen." The pathology report concluded that the biopsy showed "no evidence of chronic interstitial lung disease in the background." Staining of the biopsy specimens for acid-fast bacilli (AFB) was negative. Surprisingly, pleural fluid culture isolated Mycobacterium abscessus which was also isolated from 1 gastric aspirate. At this time, Pediatric Infectious Diseases service was consulted. Susceptibility testing was performed in our local microbiology lab and after initiation of therapy for M. abscessus with amikacin (11 mg/kg/dose q24 h), clarithromycin (10 mg/kg/dose q12 h) subsequent AFB smears and cultures from bronchoalveolar lavage were negative. As inducible macrolide resistance for M. abscessus isolates has been reported, imipenem-cilastatin (20 mg/kg/dose q12 h) was initiated despite the isolate's MIC reported to be >32 mug/mL, while awaiting erm(41) gene testing results performed at the Mycobacteria/Nocardia lab at the University of Texas Health Science Center at Tyler. A nonfunctional erm(41) gene was identified by sequencing, confirming clarithromycin susceptibility (Figure 2). Imipenem was discontinued after several weeks as the patient developed transaminitis, which resolved after discontinuation.
Due to the microbiology findings and severity of the patient's clinical presentation, further immune system function evaluation was undertaken with Pediatric Immunology consultation. HIV antibody and HIV RNA PCR testing were negative. Neutrophil oxidative index to evaluate for chronic granulomatous disease was normal. Lymphocyte phenotyping and mitogen and antigen proliferation studies were normal. She did demonstrate polyclonal hypergammaglobulinemia. However, she had normal antibody responses to diphtheria, tetanus, and 23-valent pneumococcal polysaccharide vaccine administration. Additionally, sweat chloride testing for cystic fibrosis was normal. At this point, Pediatric Pulmonology concluded that underlying lung pathology was unlikely. Consultants from Pediatric Medical Genetics requested urine organic acid and serum amino acid levels which were normal. She was assessed for aspiration that could contribute to her disease (bronchoscopy, barium swallow, and pH probe), but all studies were normal. Nerve conduction study showed no electrodiagnostic evidence to suggest an underlying neuropathy, myopathy, or neuromuscular junction defect.
Despite the normal evaluation to this point, we remained concerned about immunodeficiency or other genetic disease increasing susceptibility to nontuberculous mycobacteria (NTM) infection. Whole blood was sent to Dr. Steve Holland (Division of Intramural Research (DIR) at National Institute of Allergy and Infectious Diseases (NIAID)) to assess for potential Mendelian susceptibility to mycobacterial disease (interferon gamma receptor/STAT 1 gene deficiency). Whole exonic captures and analysis of 3635 regions spanning 342 genes were evaluated, though 874 regions corresponding to 250 genes had "inadequate or incomplete coverage." With these limitations, no obvious causative variants were identified from the captured regions screened. Three "uncommon heterozygous variants of unknown significance" were identified (LRBA, RNASEH2Bm, and LYST) as well as one novel heterozygous variant of unknown significance (TMC8). A second whole-exome sequencing test (ExomeNext , Ambry Genetics , Aliso Viejo, CA) requested by Medical Genetics reported "no clinically relevant alterations detected."
Over her 4-month hospitalization (complicated by central-line associated bloodstream infection and respiratory syncytial virus infection), her respiratory support was weaned to continuous positive airway pressure and she was discharged with supplemental oxygen via nasal cannula. Repeat computed tomography imaging of the chest was obtained after 7 months of treatment and showed improvement of the bilateral consolidations. Serial chest radiographs revealed marked improvement with only subsegmental atelectasis in the right lung base at 15 months of age. Ultimately, she completed 14 months of amikacin and clarithromycin, and oxygen supplementation via nasal cannula was discontinued. She has normal weight gain and growth parameters at this time. Her hearing tests have been normal.