Index of Suspicion in the Nursery
3 Term Infant With Severe Respiratory Failure
AUTHOR DISCLOSURE Dr Alsaleem’s
affiliation at time of publication is Children’s
Mercy Hospital, and the University of Kansas,
Kansas City, KS Drs Alsaleem, Hpa, and
Kozielski, have disclosed no financial
relationships relevant to this article. This
commentary does not contain a discussion
of an unapproved/investigative use of a
commercial product/device.
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Mahdi Alsaleem, MD,* Nja Hpa, MD,* Rafal Kozielski, MD†
*Neonatal-Perinatal Medicine and †Pediatric Pathology, The State University of New York,
University at Buffalo, Buffalo, NY
CASE PRESENTATION
A female neonate born at 39 weeks of gestation is transferred from the well
newborn nursery 7 hours after birth because of apnea and cyanosis. The infant is
born via elective repeat cesarean section. The pregnancy had been complicated
by chronic hypertension and gestational diabetes mellitus. Maternal medications
during pregnancy were labetalol and metformin. The maternal perinatal screen-
ing results were unremarkable. Membranes ruptured at the time of delivery.
Apgar scores are 9 and 9 at 1 and 5 minutes, respectively. Arterial cord pH is 7.29,
with a base deficit of
4.3. The infant appears well after delivery, and hence is
transferred to the newborn nursery to remain with the mother. Around 7 hours
after birth, the infant is cold, and her temperature is <34°C. At the same time, she
has apnea and severe cyanosis. She is not improving with positive pressure
ventilation. She subsequently undergoes intubation and is admitted to the NICU
for further evaluation and management.
On admission, the infant’s physical examination shows her weight to be 2,690 g
(11th percentile), temperature 96.8°F (36°C), and heart rate 147 beats/min. She is noted
to have tachypnea, with a respiratory rate of 68 breaths/min, and oxygen saturation of
85% on 50% fraction of inspired oxygen. The rest of the physical examination shows
normocephalic head with no signs of trauma. The retinal examination findings are
normal. Breath sounds are equal and clear in both lungs. Cardiovascular examination is
remarkable for grade 2 systolic murmur, best heard at the left upper sternal border.
Neurologic examination finds lethargy and decreased spontaneous activity.
Laboratory Studies
Laboratory tests performed on admission are shown in the Table.
Radiologic Investigations and Other Studies
Chest radiography shows mildly hypoinflated lungs with mild bilateral haziness.
No focal consolidation, pleural effusion, or pneumothoraces are seen. The cardio-
thymic silhouette appears within normal limits. Ultrasonography of the head is
unremarkable.
Given the significant unexplained hypoxemia, echocardiography is ordered.
Results suggest normal cardiac structure, pulmonary hypertension, dilated right
side of the heart, and right-to-left shunting across the patent ductus arteriosus
and patent foramen ovale. At least 2 pulmonary veins are seen entering the left
atrium. Bilateral ventricular functions are normal. There is no evidence of peri-
cardial tamponade.
Hospital course (Fig 1), combined with biopsy results (Fig 2), confirms the
diagnosis.
Vol. 21 No. 5 MAY 2020 e349
 TABLE. Initial Laboratory Test Results on Admission
COMPLETE BLOOD CELL COUNT BLOOD CHEMISTRY ARTERIAL BLOOD GAS
9
White blood cell count, 24,500/mL (24.510 /L) Sodium, 141 mEq/L pH, 7.09
Hemoglobin, 20.1 g/dL (201 g/L) Potassium, 5.6 mEq/L PCO2, 44 mm Hg
Hematocrit, 57% Chloride, 109 mEq/L PO2, 55 mm Hg
3 9
Platelets, 28310 /mL (28310 /L) Bicarbonate, 15 mEq/L Base deficit, 16
Immature to total neutrophil ratio, 28% Blood urea nitrogen, 13 mg/dL (4.6 mmol/L) Oxygenation index, 8.7
Creatinine, 0.74 mg/dL (65.4 mmol/L)
Calcium, 9.5 mg/dL (2.4 mmol/L)
Glucose, 94 mg/dL (5.2 mmol/L)

Differential Diagnosis echocardiography showed worsening pulmonary hyperten-

• Sepsis sion. After maximizing the medical support for pulmonary
• Idiopathic persistent pulmonary hypertension of the hypertension, with no improvement, she was placed on
newborn extracorporeal membrane oxygenation (ECMO) on day 3
• Inborn error of metabolism after birth. Attempts to wean ECMO support were unsuc-
• Congenital surfactant dysfunction cessful. Subsequently, a lung biopsy was performed, which
• Alveolar capillary dysplasia revealed the diagnosis of ACD/MPV. After discussing the
• Congenital cardiomyopathy futility of care with the family, the caregivers elected to
• Congenital neuromuscular disorders withdraw support at 4 weeks of age (Fig 1).

Actual Diagnosis
Alveolar capillary dysplasia with misalignment of the pul-
monary veins (ACD/MPV)
PATIENT COURSE
The infant’s condition deteriorated with time. Respiratory
support was escalated to high-frequency ventilation. Serial
DISCUSSION
ACD/MPV is a rare, untreatable lung disease that results in
severe respiratory failure and ultimately death in most cases.
(1) This entity was first described in 1947, (2) but only more
than 100 cases have been reported in the literature. The
diagnosis of ACD/MPV can be missed in cases of severe
idiopathic pulmonary hypertension when a biopsy is not
performed or in cases of unexplained neonatal death. (2)

Figure 1. Timeline and clinical manifestations of the infant presented in this case. ECMO¼extracorporeal membrane oxygenation; FiO2¼fraction of
inspired oxygen concentration; HR¼heart rate; MAP¼mean airway pressure; SpO2¼oxygen saturation.

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Figure 2. Congested misaligned pulmonary veins (V) positioned adjacent to thickened pulmonary arteries (Ar) within acinar parenchyma. Pulmonary
capillaries (C) are dysplastic, decreased in number, and abnormally placed away from the alveolus (A). (20 objective, H&E stain).

Multiple theories exist to explain the association Diagnosis

between ACD/MPV and severe pulmonary hypertension,
including abnormal development during fetal lung vas-
cularization, which can result in obstruction and pulmo-
nary hypertension. (3) Others have suggested that the
decreasing number and misalignment of the pulmo-
nary capillaries occurred as a result of severe arterial
constriction. (4)
Clinical Presentation
Most infants with ACD/MPV are asymptomatic full-term
neonates with good Apgar scores at birth. This asymptom-
atic period is usually followed by cyanosis, respiratory
distress, and hypoxia suggestive of acute respiratory failure
within the first 24 hours after birth. Transient short-term
improvement of the clinical condition may occur after
starting standard management for persistent pulmonary
hypertension of the newborn. Subsequently, respiratory
failure worsens and clinical course deteriorates, necessi-
tating ECMO in most cases. Attempts to wean ECMO
support are usually unsuccessful. In such cases, clinicians
should strongly consider lung biopsy to evaluate for ACD/
MPV and other untreated causes of severe respiratory
failure.
Radiologic imaging usually is nonspecific, and in the major-
ity of the cases, findings are reported as normal. Imaging
can show mild bilateral haziness with slight granularity.
Echocardiography shows evidence of pulmonary hyperten-
sion. Recent literature suggested an association between the
FOXF1 gene and ACD/MPV. (5) The gold standard diagnos-
tic test for ACD/MPV diagnosis is lung biopsy, which shows
decreased and abnormally located pulmonary capillaries,
thickened muscular arterial wall, misaligned and congested
pulmonary veins, and thickening of the alveolar septum (Fig 2).
Treatment
Treatment options are mainly targeted toward the associated
pulmonary hypertension. The initial short-lasting response
followed by rapid deterioration will give a clue to ACD/MPV
diagnosis. ECMO is usually an ineffective last resort for
management. Lung transplantation is the only theoretical
treatment option that could result in a better outcome;
however, the small size, instability, and critical condition
of neonates with ACD/MPV make lung transplantation less
feasible. As discussed earlier, the prognosis is dismal, with a
high risk of mortality in neonates. (6) Death usually occurs
within the first few weeks after birth.

Vol. 21 No. 5 MAY 2020 e351

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 Lessons for the Clinician
• In neonates with respiratory failure unresponsive to the
standard therapeutic interventions, ACD/MPV should be
in the differential diagnosis.
• Lung biopsy should be considered in infants with severe
pulmonary hypertension unresponsive to ECMO.
• Diagnosis of ACD/MPV carries high mortality; discussion
of withdrawal of care with the family is recommended to
avoid futile and invasive interventions.
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Recognize the clinical features and differential diagnosis of
persistent pulmonary hypertension.
• Recognize the laboratory, imaging, and other diagnostic features
of persistent pulmonary hypertension.
• Know the management of persistent pulmonary hypertension
including assisted ventilation, pharmacologic approaches, and
ECMO.
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References
1. MacMahon HE. Congenital alveolar dysplasia of the lungs.
Am J Pathol. 1948;24(4):919–931
2. Bishop NB, Stankiewicz P, Steinhorn RH. Alveolar capillary
dysplasia. Am J Respir Crit Care Med. 2011;184(2):172–179
3. Cater G, Thibeault DW, Beatty EC Jr, Kilbride HW, Huntrakoon M.
Misalignment of lung vessels and alveolar capillary dysplasia: a cause
of persistent pulmonary hypertension. J Pediatr.
1989;114(2):293–300
4. Sirkin W, O’Hare BP, Cox PN, Perrin D, Cutz E, Silver MM. Alveolar
capillary dysplasia: lung biopsy diagnosis, nitric oxide
responsiveness, and bronchial generation count. Pediatr Pathol Lab
Med. 1997;17(1):125–132
5. Stankiewicz P, Sen P, Bhatt SS, et al. Genomic and genic deletions of
the FOX gene cluster on 16q24.1 and inactivating mutations of
FOXF1 cause alveolar capillary dysplasia and other malformations.
Am J Hum Genet. 2009;84(6):780–791
6. Deutsch GH, Young LR, Deterding RR, et al; Pathology Cooperative
Group; ChILD Research Co-operative. Diffuse lung disease in
young children: application of a novel classification scheme.
Am J Respir Crit Care Med. 2007;176(11):1120–1128
Suggested Reading
Arzuaga BH, Mathai T, Khan O. Children’s interstitial lung diseases in
early infancy. NeoReviews. 2013;14(11), e562–e566. doi: 10.1542/
neo.14-11-e562
 Case 3: Term Infant With Severe Respiratory Failure
Mahdi Alsaleem, Nja Hpa and Rafal Kozielski
NeoReviews 2020;21;e349
DOI: 10.1542/neo.21-5-e349

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 Case 3: Term Infant With Severe Respiratory Failure
Mahdi Alsaleem, Nja Hpa and Rafal Kozielski
NeoReviews 2020;21;e349
DOI: 10.1542/neo.21-5-e349

The online version of this article, along with updated information and services, is
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