Pediatric patients with respiratory signs and symptoms who are found to be wheezing present a diagnostic dilemma to pediatricians. The majority of these cases are diagnosed as some degree of reactive airway disease, either as viral bronchiolitis or asthma. In this scenario, a patient with wheezing was initially given 2 courses of appropriate antibiotics on the basis of the duration and concurrence of other symptoms. However, he was subsequently referred to a pediatric pulmonologist for further workup after failure to improve and persistent oxygen saturations in the low-to-mid 90s. More extensive testing was completed by the pediatric pulmonologist, in addition to a short hospital admission. A rigid bronchoscopy was eventually completed, which revealed small pieces of partially digested material. Although his persistent cough resolved, his saturations continued to be suboptimal. A chest computed tomography scan with contrast was then completed, which eventually led to his diagnosis and appropriate treatment and resolution of his symptoms.

A 2 and-a-half–year-old previously healthy boy presented to his pediatrician for a clinic visit after 9 days of a dry, nonproductive cough, posttussive emesis, and intermittent fevers. He was maintaining adequate urine output but had decreased solid food intake. He was not taking any daily medications and had never been hospitalized. No illnesses were common in the family on his mother’s side, but the father’s family history was not known at the time of the first encounter because he was currently stationed in South Korea. He was fully immunized. He had smoke exposure at home and also had 2 dogs. On physical examination, he was well nourished and normally developing. There was mild left-sided wheezing, but he was breathing comfortably. There was no evidence of digital clubbing or peripheral or central cyanosis. His vitals were as follows: temperature: 37.5°C (99.5°F); heart rate: 100 beats per minute; respiration rate: 18; Spo2: 97%; height: 92.2 cm (44th percentile); weight: 14.2 kg (63rd percentile). What diagnoses are you considering, Dr Viehl?

Cough, posttussive emesis, and fever for more than a week can be caused by a number of conditions, but the most likely would be viral bronchiolitis from respiratory syncytial virus or human metapneumovirus, particularly given the presence of wheezing.1  An atypical pneumonia is also common and should be considered highly. Other possibilities include a community-acquired pneumonia, although the lack of crackles auscultated on examination argues against this diagnosis. Posttussive emesis and prolonged cough are also suggestive of infection with Bordetella pertussis. Although he is vaccinated, there is variable vaccine effectiveness, and although mostly a seasonal infection, pertussis does occur year-round.2  Aspiration pneumonia is a possibility even without a witnessed or concerning event, given the presence of unilateral wheezing, especially in this age group. Because he is on day 9 of illness and does not seem to be improving, azithromycin would be an appropriate antibiotic choice to cover atypical pathogens such as Mycoplasma pneumoniae.3  Is there anything we are not covering or anything else you are concerned about, Dr Estabrook?

Given the child’s prolonged, relatively mild symptoms, I agree that the most likely infectious etiologies are community-acquired respiratory viruses, Mycoplasma, and pertussis. Another possibility is an endemic fungal infection, such as Histoplasmosis. It is also a good idea to get a thorough travel and exposure history including tuberculosis. Has he lived or traveled to areas where Coccidioidomycosis is endemic or played in a barn, cave, or chicken coop? Was his mother screened for HIV infection during his pregnancy?

He returned to clinic 4 days later with only mild improvement in symptoms. A thorough exposure history was obtained at this visit. The pregnancy was uncomplicated, and his mother’s prenatal serologies were unremarkable, including a negative HIV-screen result. He had not traveled outside the state of Missouri recently and lived in the suburbs. He had not been exposed to anyone who had recently been in prison or visited any farms, caves, or chicken coops. Now, he was eating slightly more than before. However, he was still having intermittent fevers and episodes of coughing. His oxygen saturation was 94%. He had faint crackles on the left side and the same degree of wheezing auscultated previously.

Because there has not been appreciable improvement with the macrolide, I am now more concerned that this is an evolving community-acquired pneumonia, particularly given that crackles were auscultated on examination. The macrolide would not have great coverage against those bacteria commonly implicated in community-acquired pneumonia, such as Streptococcus pneumoniae. I would recommend changing his antibiotic to amoxicillin-clavulanic acid, although there is not great evidence to support a specific regimen.4  A foreign body aspiration is also still a possibility, which is why amoxicillin alone would not suffice. A chest radiograph is warranted as well, and the results will yield more information. Dr Bhalla, does the chest radiograph reveal anything?

A 2-view chest radiograph reveals mild hyperexpansion but is otherwise unremarkable. No consolidation, pleural effusion, or interstitial process is seen.

A course of amoxicillin-clavulanic acid was prescribed, but the patient did not improve.

Dr Estabrook, we have now tried 2 courses of antibiotics without any appreciable improvement. Should we start to worry about antibiotic resistance?

My suspicion that this is an inadequately treated bacterial pneumonia is low, given his course and lack of consolidation on chest radiograph. Methicillin-resistant Staphylococcus aureus and highly drug resistant S pneumonia would be the most likely organisms not covered by the antibiotics he received but are not consistent with this clinical picture.

Dr Lee, what else can we do for this patient?

The patient has not improved on 2 courses of antibiotics that cover the majority of organisms responsible for typical and atypical pneumonias in this age group. He continues to have symptoms of fever, cough, and wheezing and now has crackles and persistent mild hypoxemia. Diagnostic considerations that should be entertained at this point include complications of pneumonia and underlying conditions that might predispose one to have a complication (eg, immunodeficiency, cystic fibrosis, airway malformation, etc) as well as a retained foreign body. Although the repeat chest radiograph did not reveal signs of a foreign body, it is worth noting that plain films have poor sensitivity for this.

To evaluate the other diagnostic considerations, further evaluation should include a complete blood cell count, sweat chloride test, quantitative immunoglobulin levels (immunoglobulin G, immunoglobulin A, immunoglobulin M, and immunoglobulin E) as well as pneumococcal, tetanus, and Haemophilus influenzae type B titers. A repeat chest radiograph is reasonable at this time to monitor possible progression or complications of pneumonia. The concern for an immunodeficiency or cystic fibrosis is a reasonable consideration, but because he has no history of frequent or prolonged infections nor an inability to gain weight these are less likely. Additionally, having had a normal newborn screen would decrease the likelihood of cystic fibrosis and some immunodeficiencies. Aspiration of a foreign body, as you pointed out, is more likely,5  given his age and the presence of unilateral wheezing on initial presentation. A chronic disease leading to his hypoxemia remains on the differential. An additional history regarding potential environmental exposures would also be helpful. Dr Bhalla, did you notice anything on repeat imaging?

A repeat 2-view chest radiograph is unchanged from the previous examination 8 days previous. The lungs remain clear.

The laboratory tests mentioned above were sent and were all within normal limits. An additional history was obtained, revealing that the child lived in the basement of his maternal grandparent’s home, which was described as well ventilated and dry. The repeat chest radiograph revealed minimal perihilar infiltrates, without evidence of pneumonia, hyperinflation, or a foreign body. After these results, he was started on a 5-day course of prednisone. Three days later, he had an episode of respiratory distress characterized by shortness of breath and wheezing after running around in the park for a short period of time.

It sounds like we may not be getting to the true cause of his persistent wheezing and persistent, nonproductive cough. Do you think a hospital admission would be justified at this point?

A hospital admission should be pursued to further investigate the cause of his respiratory symptoms, including shortness of breath, wheezing, and hypoxemia at rest. The course of steroids should be continued. Albuterol may be administered to assess for improvement in wheezing. Additional diagnostic studies to be considered include an echocardiogram to evaluate cardiac anatomy and function and a barium esophagram to exclude the possibility of anatomic abnormalities (eg, vascular sling or ring, tracheoesophageal fistula, etc). Other potential diagnoses include the presence of a bronchopulmonary sequestration or congenital pulmonary airway malformation, which are not infrequently brought to light with infection in this age group. A bronchoscopy should be arranged to evaluate for a possible retained foreign body and visualize his airways directly. A computed tomography (CT) scan could be considered, but we will begin with a staged approach. These should be performed during this hospitalization and not pursued on an outpatient basis because of consideration for these rarer diagnoses and his hypoxemia at rest.

A barium esophagram and echocardiogram were both normal. A rigid bronchoscopy revealed 2 small pieces of vegetable-like material in his right bronchus intermedius. These were removed, and he was discharged from the hospital on a prednisone taper, amoxicillin/clavulanic acid for infection prophylaxis, with a diagnosis of foreign body aspiration.6  A repeat course of amoxicillin/clavulanic acid would still be warranted because source control with removal of the foreign body has just been obtained. At his follow-up clinic visit 4 weeks later, the parents were pleased to report that his persistent, episodic cough had resolved completely. However, his mother noted that he continued to have dyspnea with even mild exertion, and his oxygen saturation in clinic remained in the low-to-mid 90s.

Generally speaking, outside of shock or altered cardiac output states (eg, anemia, etc), there are 5 mechanisms of hypoxemia. These include hypoventilation, ventilation and perfusion (V/Q) mismatch, diffusion impairment, right-to-left shunt, and low inspired fraction of inspired oxygen. In our patient, low inspired fraction of inspired oxygen can be immediately ruled out, but the remaining 4 mechanisms should still be considered. A V/Q mismatch can occur with pneumonias, airway obstructions, or vascular anomalies. Causes of hypoventilation include central controller dysfunction (eg, congenital central hypoventilation syndrome, etc) as well as neuromuscular disorders (eg, muscular dystrophies, severe scoliosis, etc). Diffusion impairment can occur in various interstitial lung diseases, several of which are caused by abnormalities in surfactant homeostasis. Shunts that lead to hypoxemia can be divided into those that occur within the lungs (eg, arteriovenous malformations [AVMs], etc) versus outside the lungs (intracardiac lesions). Anemia and hemoglobinopathies are additional potential etiologies for hypoxemia, but the patient had no history or laboratories to support these diagnoses. As such, a chest CT scan with contrast should be obtained next to evaluate the etiology of his hypoxemia and dyspnea. This will help to look for sequestration, airway malformations, and vascular anomalies. Table 1 summarizes the evaluation of suspected pulmonary causes of hypoxemia and dyspnea. Dr Bhalla, do you notice anything on the CT scan?

TABLE 1

Evaluation of Suspected Pulmonary Causes of Hypoxemia and Dyspnea

DiagnosisDiagnostic Test(s) of Choice
Bronchiolitis Clinical findings and viral swab 
Bronchopulmonary sequestration Chest CT 
Congenital pulmonary airway malformation Chest CT 
Cystic fibrosis Sweat chloride 
Foreign body aspiration Rigid bronchoscopy and chest CT 
Immunodeficiency Immunoglobulin titers, vaccine titers, and flow cytometry (B- and T-cell subsets) 
Pneumonia (and complications) Chest radiograph and chest CT 
Vascular malformations (ring, sling, AVMs, etc) Barium swallow and chest CT with contrast 
DiagnosisDiagnostic Test(s) of Choice
Bronchiolitis Clinical findings and viral swab 
Bronchopulmonary sequestration Chest CT 
Congenital pulmonary airway malformation Chest CT 
Cystic fibrosis Sweat chloride 
Foreign body aspiration Rigid bronchoscopy and chest CT 
Immunodeficiency Immunoglobulin titers, vaccine titers, and flow cytometry (B- and T-cell subsets) 
Pneumonia (and complications) Chest radiograph and chest CT 
Vascular malformations (ring, sling, AVMs, etc) Barium swallow and chest CT with contrast 

A chest CT scan performed with intravenous contrast revealed 2 AVMs (Fig 1). The larger one in the left lower lobe (LLL) is more complex, with multiple feeding arteries that are 3 mm or greater in size. The right middle lobe (RML) AVM is simple, with only 1 feeding artery. The malformations do not reveal any signs of adjacent hemorrhage.

FIGURE 1

A total of 2 AVMs are visible, 1 in the RML and another in the LLL.

FIGURE 1

A total of 2 AVMs are visible, 1 in the RML and another in the LLL.

Close modal

The patient was referred to the hereditary hemorrhagic telangiectasia (HHT) center. Additional history was obtained during this clinic visit from the father, who had recently returned from South Korea. The patient’s father described having similar symptoms and recalled several family members with similar malformations in the lungs, including the patient’s paternal grandmother and paternal great grandfather. The diagnosis of Osler-Weber-Rendu syndrome (HHT) was made.

Shortly after diagnosis, the child underwent a pulmonary artery angiogram with embolization of the 2 pulmonary AVMs (Figs 23). Oxygen saturations subsequently improved to >98%. In addition, his mother noticed that he had “three times as much energy.” His mother now noticed the first cutaneous telangiectases overlying his right thenar eminence. He underwent a brain MRI that did not reveal any intracranial AVMs and abdominal MRI that did not reveal any intrabdominal or hepatic malformations.

FIGURE 2

Pulmonary AVM in the RML, measuring ∼4 mm in diameter.

FIGURE 2

Pulmonary AVM in the RML, measuring ∼4 mm in diameter.

Close modal
FIGURE 3

Pulmonary AVM in the LLL; an AVM in the RML status post coiling is visible.

FIGURE 3

Pulmonary AVM in the LLL; an AVM in the RML status post coiling is visible.

Close modal

Over the next few years, he experienced intermittent episodes of epistaxis, an increasing number of cutaneous telangiectases, and a new malformation in his LLL that caused persistently low oxygen saturations. He underwent embolization of this new vascular malformation, with improvement of his saturations to the upper 90s. However, within the next 12 months his exercise capacity again diminished, with a decrease in his oxygen saturations to the high 80s and low 90s at his primary care clinic visits. A repeat chest CT scan revealed numerous small malformations in his LLL. The cardiothoracic surgery department was consulted and the decision was made to proceed with a left lower lobectomy. He underwent this operation and had subsequent resolution of his exercise intolerance and chronic hypoxemia. He has not experienced a return of his symptoms since the surgery and is still followed approximately every 3 years. To date, no new malformations have been identified. It should be noted that the foreign body aspiration that ultimately led to the diagnosis of Osler-Weber-Rendu syndrome was a classic red herring. Also, no additional diagnostic criteria, such as recurrent epistaxis or cutaneous telangiectases, were noted until well after the diagnosis was firmly established.

This is not the diagnosis I expected when this case was first presented. Dr White, is there anything you tell patients with Osler-Weber-Rendu syndrome about recurrence of symptoms, extrapulmonary manifestations, or future family planning?

HHT is a relatively common but underrecognized illness, affecting in 5000 people in the United States. It is manifested by the classic symptoms of frequent nosebleeds, telangiectatic blood vessels in classic locations (such as the lips, tongue, and hands), and solid organ AVMs, occurring most often in the lungs and brain.7  It is an autosomal dominant disorder, with variable penetrance, and is often not recognized by physicians because of the mundane nature of the symptoms. Indeed, children have fewer recognizable symptoms than do adults (in particular, epistaxis and telangiectasia, both of which tend to worsen as patients with HHT age), and, although it is unclear exactly when in life AVMs develop, it appears likely that some are congenital and some develop over time.

Minor symptoms include epistaxis, telangiectasia, and shortness of breath. A migraine headache may also occur. More serious symptoms include hemoptysis, ischemic stroke, hemorrhagic stroke, or brain abscess.8  The potential severity of these complications is such that many physicians taking care of adult patients with HHT will proactively screen for the presence of pulmonary and cerebral AVMs and treat them to avoid sequelae. In children, the indications for screening and treatment are less straightforward, and there are concerns that early intervention may lead to more complications later in life, such as collateral vessel formation, stimulation of additional and new AVMs, or induction of ischemia from the procedure itself. These risks must be weighed carefully against the option of no intervention, and, although the incidence of stroke or brain abscess is small, it is not zero. New international guidelines focused on the diagnosis and management of HHT were recently published and include pediatric-specific recommendations.9 

Symptoms are likely to progress slowly over years to decades, as both the number and size of telangiectases increase, leading to nosebleeds that are more frequent and the development of gastrointestinal bleeding from mucosal telangiectases and anemia. AVMs themselves may grow or new ones may develop, leading to an increasing risk for hemorrhage, stroke, and abscess. Pulmonary AVMs as well tend to become more apparent over time as they lead to more V/Q mismatch and hypoxemia. Most patients, however, are relatively asymptomatic. As an autosomal dominant disorder, families are counseled that each child has a 50% chance of inheriting the disease-causing mutation, although we point out that there is much variable penetrance.10  Pregnant women with HHT themselves often develop worsening disease, and their pregnancies should be considered high-risk.11 

Dr Viehl wrote the initial draft of this manuscript, recruited the involved subspecialists, and finalized the manuscript before submission; Dr Estabrook contributed as the infectious disease opinion; Dr Bhalla contributed as the radiology opinion; Drs Lee and Kemp contributed as the pulmonology opinion; Dr White contributed as the hereditary hemorrhagic telangiectasia specialist and obtained a signed document of consent from the patient’s family; and all authors approved the final manuscript as submitted.

FUNDING: No external funding.

AVM

arteriovenous malformation

CT

computed tomography

HHT

hereditary hemorrhagic telangiectasia

LLL

left lower lobe

RML

right middle lobe

V/Q

ventilation and perfusion

1
Zorc
JJ
,
Hall
CB
.
Bronchiolitis: recent evidence on diagnosis and management
.
Pediatrics
.
2010
;
125
(
2
):
342
349
2
Leber
AL
.
Pertussis: relevant species and diagnostic update
.
Clin Lab Med
.
2014
;
34
(
2
):
237
255
3
McCulloh
RJ
,
Patel
K
.
Recent developments in pediatric community-acquired pneumonia
.
Curr Infect Dis Rep
.
2016
;
18
(
5
):
14
4
Wubbel
L
,
Muniz
L
,
Ahmed
A
, et al
.
Etiology and treatment of community-acquired pneumonia in ambulatory children
.
Pediatr Infect Dis J
.
1999
;
18
(
2
):
98
104
5
Rovin
JD
,
Rodgers
BM
.
Pediatric foreign body aspiration
.
Pediatr Rev
.
2000
;
21
(
3
):
86
90
6
Divisi
D
,
Di Tommaso
S
,
Garramone
M
, et al
.
Foreign bodies aspirated in children: role of bronchoscopy
.
Thorac Cardiovasc Surg
.
2007
;
55
(
4
):
249
252
7
Shovlin
CL
,
Guttmacher
AE
,
Buscarini
E
, et al
.
Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome)
.
Am J Med Genet
.
2000
;
91
(
1
):
66
67
8
Donaldson
JW
,
McKeever
TM
,
Hall
IP
,
Hubbard
RB
,
Fogarty
AW
.
Complications and mortality in hereditary hemorrhagic telangiectasia: a population-based study
.
Neurology
.
2015
;
84
(
18
):
1886
1893
9
Faughnan
ME
,
Mager
JJ
,
Hetts
SW
, et al
.
Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia
.
Ann Intern Med
.
2020
;
173
(
12
):
989
1001
10
Abdalla
SA
,
Letarte
M
.
Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease
.
J Med Genet
.
2006
;
43
(
2
):
97
110
11
Shovlin
CL
,
Sodhi
V
,
McCarthy
A
,
Lasjaunias
P
,
Jackson
JE
,
Sheppard
MN
.
Estimates of maternal risks of pregnancy for women with hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): suggested approach for obstetric services
.
BJOG
.
2008
;
115
(
9
):
1108
1115

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.