To the Editor, We report the case of a 4-year-old girl with cystic fibrosis (CF) whose life and premature death highlights inadequacies in early diagnosis and clinical care, especially for advanced lung and liver disease. Born at term to Hispanic parents (parent-reported race) at an urban hospital, she had an elevated Immunoreactive Trypsinogen (IRT) level (126.9 ng/mL), but Cystic Fibrosis Transmembrane Conductive Regulator (CFTR) variants were not identified. Misinterpretation of the “no mutations” result led to a missed CF diagnosis. Respiratory symptoms and failure-to-thrive were managed as asthma until her first hospitalization at 18 months for acute hypoxemic respiratory failure (AHRF). Recurrent symptoms prompted investigation, and she was diagnosed with CF at age three based on elevated sweat chloride levels (107/107 mmol/L, normal A, W1089X). Malnutrition (weight z-score −1.63), severe pancreatic insufficiency (Fecal elastase < 10 μg/g), vitamin deficiencies, Pseudomonas aeruginosa isolation from bronchoalveolar lavage, and imaging showing diffuse bronchiectasis (Figure 1) confirmed disease severity. Six months later, development of splenomegaly and progressive thrombocytopenia prompted evaluation for CF hepatobiliary involvement (CFHBI). Pertinent findings included: elevated transaminases, advanced cirrhosis by MR elastography (10.99 kPa) and portal hypertension with full-column esophageal varices (Figure 2a). Liver biopsy revealed cirrhosis along with features atypical for CF including bile lakes and bile duct proliferation (Figure 2b). This prompted genetic investigation revealing a Polycystic Kidney and Hepatic Disease 1 (PKHD1) variant associated with congenital hepatic fibrosis that was felt to contribute to her advanced CF Liver Disease (aCFLD). Due to her aCFLD, she was listed for liver transplantation. However, given her preserved hepatic synthetic function, her natural Pediatric End-Stage Liver Disease (PELD) scores were low and did not meet automatic exemption criteria. Despite multiple attempts, only a slight increase in PELD score was granted by exemption points, prolonging her transplant wait and leading to recurrent multi-organ morbidity with temporary transplant list deactivation. Progressive abdominal distension impacted lung volumes and severe thrombocytopenia increased bleeding risk, thereby impairing airway clearance resulting in worsening bronchiectasis, activity endurance, and respiratory insufficiency. Despite enteral supplements, she remained severely malnourished. Gastric varices precluded gastrostomy tube placement. Despite excellent multidisciplinary care, she required near-monthly hospitalizations for CF associated complications. A 6-month Ivacaftor trial, based on minimal CFTR function restoration via nasal cell theratyping, showed no clinical benefit. At 4.5 years of age, she was hospitalized for RSV-related AHRF, recalcitrant thrombocytopenia (34→7 ×103/uL), coagulopathy (INR 2.3→10), severe malnutrition (mid-upper arm circumference z-score: −3.63), and multisystem complications requiring intubation with high ventilatory support, broad-spectrum antibiotics, total parenteral nutrition, multiple transfusions, plasma exchange, and hemodialysis. She had intermittent pulmonary hemorrhage, including one severe episode requiring bronchial artery embolization. Liver function was supported by plasmapheresis, and when stabilized from a pulmonary perspective, she was reactivated for liver transplantation at 1B status. Left lateral segmental liver transplantation from a suitable deceased donor was performed uneventfully until reperfusion. Acute portal vein thrombosis, hypothermia, and severe coagulopathy resulted in pulmonary hemorrhage and severe hemorrhagic shock. Patient was aggressively volume repleted and stabilized for 12 h, until persistent bleeding from the surgical site and pulmonary hemorrhage led to unrecoverable hypovolemic shock and cardiopulmonary arrest. The lives of people with cystic fibrosis (pwCF) have transformed significantly through newborn screening (NBS), multidisciplinary care, highly effective modulator therapies (HEMT), and impactful research 1. However, emerging evidence of delays in NBS processes, clinical care, and modulator access among pwCF of minority populations, reveal worse pulmonary, nutritional, and hepatobiliary outcomes 2, 3. Through this young child's story, we highlighted missed opportunities and systemic inadequacies in (1) early CF diagnosis and treatment, (2) universal HEMT access, (3) recognition of early aCFLD, and (4) access to liver transplantation in children with CF. IRT is the first-tier biomarker of NBS protocols with state-varied secondary genetic panels that often exclude rare or population-specific variants. Lower frequency of F508del variant and a higher prevalence of unique variants not included in targeted panels delay timely diagnosis among pwCF of non-White races 2. These include nonsense, highly pathogenic variants, such as W1089X, which are not modulator responsive. Interestingly, the second (G542X) and third (3876delA) most common variants among Hispanic pwCF are severe and not modulator-eligible 1. Persistent symptoms should trigger expanded confirmatory testing despite screen-negative status, and providers should recognize that rare mutations may be associated with severe disease. The need to develop mutation-agnostic therapies that may benefit many pwCF is reiterated. Our patient displayed signs of aCFLD atypical for her age. Current CFHBI guidelines recommend laboratory evaluation but not biopsy unless diagnosis is inconclusive 4. Biopsy was pursued here to investigate etiologies for rapid disease progression, and results prompted genetic testing revealing the PKHD1 variant which contributed to her hepatic decompensation. This case underscores the value of liver biopsy in atypical presentations. Despite cognizance on disease severity, several factors impact transplant eligibility for aCFLD. PELD scoring prioritizes biochemical markers of liver dysfunction and growth parameters 5. However, patients with aCFLD rarely develop synthetic dysfunction. Although critically ill due to complications from portal hypertension, patients with aCFLD typically have low PELD scores 5. Current standard PELD exception requires a FEV1 < 40% which is rarely seen in children and if present, may predict poor post-transplant survival 5. Additionally, abdominal competition, inadequate airway clearance, malnutrition, and bleeding risk contribute to pulmonary decline. This interplay between lung and liver disease is not incorporated in PELD scoring. Therefore, patients with aCFLD who require transplantation must rely on exception letters to achieve organ allocation 5. Our patient's immediate post-operative course reflected heightened risks resulting from current organ allocation structure. In patients with aCFLD, we propose revised scoring criteria that incorporate severity of portal hypertension and extrahepatic disease, specifically pulmonary complications. In an era of early diagnosis and HEMT, this case underscores gaps in NBS and follow-through—particularly among non-White populations—leading to delayed diagnosis and unacceptable outcomes. It highlights the need to better understand CFHBI, the complex interplay between pulmonary and hepatic disease, and limitations in PELD scoring. In summary, we reiterate the value of specialized multidisciplinary care, and advocate for comprehensive NBS panels and revised transplant criteria for children with aCFLD. Grace R Paul: conceptualization, investigation, writing – original draft, visualization, writing – review and editing, supervision. Alyshah Lakhani: writing – original draft, writing – review and editing, visualization, investigation. Karen S McCoy: writing – review and editing, visualization. A Jay Freeman: investigation, writing – original draft, writing – review and editing, supervision, visualization, conceptualization. Patient and family, multidisciplinary professionals from the pulmonary, hepatology, pharmacy, radiology, liver transplant, and pediatric ICU departments. The authors have nothing to report. IRB review was waived per institutional policy (Nationwide Children's Hospital IRB). This report does not require approval by the ethics committee or written consent from the family; however, the family was informed of this submission. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Paul et al. (Wed,) studied this question.