Case Definition

Acute Idiopathic Pulmonary Hemorrhage in Infants

• Proposed Clinical Description
• Proposed Criteria for a Clinically Confirmed Case of AIPHI
• Proposed Criteria for a Probable Case of AIPHI
• Proposed Criteria for a Suspected Case of AIPHI
• Proposed Analytic Classification Scheme for AIPHI
• Comment
• References

In 1994 and 1997, CDC reported clusters of acute pulmonary hemorrhage in infants (1,2). Reviews by internal CDC and external expert panels of these investigations identified shortcomings in the conduct of the studies (3). The panels concluded that the investigations did not prove an association between acute pulmonary hemorrhage in infants and exposure to molds, specifically Stachybotrys chartarum (atra). The recommendations of these panels were outlined in the March 2000 MMWR (3).

In response to those recommendations, CDC has developed a plan to do surveillance for the condition, to conduct investigations of clusters or cases, and to do special studies. As part of these activities, CDC convened three meetings to establish a case-definition and classification scheme for the public health surveillance of acute idiopathic pulmonary hemorrhage in infants (AIPHI); recommend a standard home environmental investigation protocol; and outline a plan for the surveillance and investigation of AIPHI. A case definition of AIPHI would facilitate case finding for public health surveillance to document the burden of the condition and would allow for the conduct of studies to identify possible etiologic agents or risk factors.

This report outlines the recommended CDC case definition and classification scheme for AIPHI. Subsequent reports will detail the CDC recommendation for prospective surveillance and studies of AIPHI, and the home environment investigation approach. This case definition and case classification scheme are intended to guide surveillance for and investigations of AIPHI and are not intended as a tool for clinical management.

Proposed Clinical Description

The sudden onset of pulmonary hemorrhage in a previously healthy infant. Pulmonary hemorrhage may present as hemoptysis or finding blood in the nose or airway with no evidence of upper respiratory or gastrointestinal bleeding. Patients present with acute, severe respiratory distress or failure requiring mechanical ventilation and chest radiograph will usually demonstrate bilateral infiltrates.

Proposed Criteria for a Clinically Confirmed Case of AIPHI

A clinically confirmed case is pulmonary hemorrhage in a previously healthy infant <1 year old with a gestational age of >32 weeks, with no prior history of neonatal medical problems that could cause pulmonary hemorrhage and whose condition meets all of criteria A, B, and C.

• Criterion A: Abrupt or sudden onset of overt bleeding or frank evidence of blood in the airway.
• Criterion B: Severe presentation leading to acute respiratory distress or respiratory failure, resulting in hospitalization in a pediatric intensive care unit (PICU) with intubation and mechanical ventilation.
• Criterion C: Diffuse, bilateral pulmonary infiltrates on Chest X-ray (CXR) or Computerized Tomography (CT) of the chest.

A previously healthy infant should:

1. have been discharged from the hospital with an uneventful course prior to this presentation with bronchoalveolar hemorrhage;
2. never been previously intubated nor required respiratory support with oxygen;
3. not have evidence of physical abuse;
4. not have any bronchoscopic abnormality that would explain the bleeding if bronchoscopy was performed at admission; and
5. not have neonatal medical problems that could cause pulmonary hemorrhage such as hyaline membrane disease, respiratory distress syndrome, bronchopulmonary dysplasia, left-sided obstructive cardiac lesions (such as congenital mitral stenosis, cor triatriatum, pulmonary venoocclusive disease, persistent pulmonary hypertension of the newborn, left-to-right cardiac shunts), chronic lung disease, or previous instrumentation of the nasopharynx or airway (such as nasogastric feeding tubes, intubation, mechanical ventilation, or surfactant administration).

Criterion A: A source of bleeding from the nose and oropharynx should be ruled out at the time of admission. Abrupt or sudden onset of overt bleeding or frank evidence of blood in the airway as evidenced by:

1. Epistaxis, hemoptysis, or frank blood in the airway below the larynx at the time of visualization, not due to any medical procedure such as laryngoscopy or intubation; or,
2. Identification of hemosiderin-laden macrophages. Finding > 20% of pulmonary macrophages containing hemosiderin on broncho-alveolar lavage or biopsy specimen.

Criterion B: Severe presentation leading to acute respiratory distress or respiratory failure resulting in hospitalization in a PICU with intubation and mechanical ventilation.

Criterion C: Documentation of CXR or chest CT findings should occur within 48 hours of presentation. For the purposes of case classification unilateral or bilateral pulmonary infiltrates on CXR or chest CT will be classified as confirmed.

Proposed Criteria for a Probable Case of AIPHI

A previously healthy infant <1 year old with a gestational age of >32 weeks who:

1. has a sudden onset of bleeding from the airway (criterion A) and who was or was not in respiratory distress, and was or was not intubated, who did or did not have pulmonary infiltrates on CXR or chest CT; or,
2. died and had evidence of bleeding from the airway based on autopsy or post-mortem findings, who was in respiratory distress and would or should have been intubated in the opinion of a clinician and who has bilateral (Criterion C) or unilateral infiltrates on CXR or chest CT.

Proposed Criteria for a Suspected Case of AIPHI

A previously healthy infant who died and had evidence of bleeding from the airway based on autopsy or post-mortem findings, who did not have chest imaging studies or showed no pulmonary infiltrates on CXR or chest CT, who was or was not in respiratory distress and was or was not intubated.

Proposed Analytic Classification Scheme for AIPHI

Because of the potential for variation in the presentation of infants for each of criteria A, B and C, different case combinations may occur possibly related to the timing or duration of presentation, disease severity, pathologic process or processes, or etiologic agent or agents associated with AIPHI. Thus in table 1 [opens in new window], the case classification scheme has been expanded to reflect some likely scenarios of case presentation that could be used for data analysis. Because at this time we know very little about pulmonary hemorrhage, this analytic classification scheme may help us to gather information to better describe and understand the natural history and spectrum of AIPHI.

Comment

Blood in the airways or alveoli of humans can originate from several anatomic sites, e.g. alveoli, large or small conducting airways, and the nasopharynx and gastrointestinal tract with pulmonary aspiration. Regardless of the site from which blood enters the lung, large volumes of blood in the lungs will lead to impaired gas exchange and altered pulmonary mechanics and cause respiratory distress.

The various manifestations of pulmonary hemorrhage have been classified into a number of different syndromes. These include: diffuse pulmonary hemorrhage, pulmonary hemorrhage of the newborn (ICD-9: 770.3); hemoptysis, cough with hemorrhage, pulmonary hemorrhage not otherwise specified (ICD-9: 786.3); and idiopathic pulmonary hemosiderosis (ICD-9: 516.1). The similarity of cases represented by these diagnostic syndromes to cases that would meet the CDC case definition for AIPHI is uncertain, as is their usefulness and specificity for surveillance of AIPHI.

This definition of a case of AIPHI is intended to denote a separate entity from the syndrome pulmonary hemosiderosis. For some presentations, e.g. at autopsy, a finding of hemosiderin-laden alveolar macrophages may be used as evidence of bleeding into the lungs. A finding of > 20% of total pulmonary macrophages containing hemosiderin may be consistent with pulmonary hemorrhage (4,5) that occurred >48 hours before presentation (6).

CDC plans to use this case definition and case classification scheme to conduct reviews of state-level mortality and hospitalization data to more clearly define the magnitude of AIPHI, to determine the correlation between the current diagnostic categories for pulmonary hemorrhage and our case definition of AIPHI, and to work with state and local health departments and PICUs to investigate clusters of cases of AIPHI.

References

1. CDC. Acute pulmonary hemorrhage/hemosiderosis among infants—Cleveland, January 1993-November 1994. MMWR 1994;43:881-3.
    
2. CDC. Update: Pulmonary Hemorrhage/Hemosiderosis Among Infants—Cleveland, Ohio, 1993-1996. MMWR 1997;46:33-35.
    
3. CDC. Update: Pulmonary Hemorrhage/Hemosiderosis Among Infants—Cleveland, Ohio, 1993-1996. MMWR 2000;49:180-4.
    
4. Perez-Arellano J, Garcia JEL, Macias MCG, Gomez FG, Lopez AJ, de Castro S. Hemosiderin-laden macrophages in bronchoalveolar lavage fluid. Acta Cytologica 1992;36:26-30.
    
5. De Lassence A, Fleury-Feith J, Escudier E, Beaune J, Bernaudin JF, Cordonnier C. Alveolar hemorrhage-diagnostic criteria and results in 194 immunocompromised hosts. Am J Respir Crit Care Med 1995;151:157-163.
    
6. Epstein CE, Elidemir O, Colasurdo GN, Fan LL. Time course of hemosiderin production by alveolar macrophages in a murine model. Submitted.