depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Background
This report presents CDC's recommendations for case definitions for Acute Idiopathic Pulmonary Hemorrhage (AIPH) among infants and CDC's plan for retrospective surveillance for AIPH among infants, including a study to evaluate the feasibility of using International Classification of Diseases (ICD) (1) codes for surveillance for AIPH.
In 1994 and 1997, CDC reported clusters of acute pulmonary hemorrhage (APH) among infants (2,3) in Cleveland, Ohio. During 1992, a similar cluster occurred in the Chicago area (4). In Cleveland, risk factors for illness included male sex; lack of breast-feeding; residence in households with smokers; residence in homes where water damage had occurred during the previous 6 months; and residence in homes with increased quantities of fungi, including Stachybotrys atra.
Reviews by CDC staff and external consultants of these investigations identified shortcomings in the conduct of the studies (5). These panels concluded that the investigations did not prove an association between APH among infants and exposure to molds, specifically S. chartarum (atra). These reviewers recommended that CDC, pediatric pulmonologists, and state and local public health officials collaborate to
- develop a standard surveillance case definition;
- develop standard protocols for data collection and environmental assessment; - implement surveillance for AIPH; - investigate cases of AIPH among infants, particularly when clusters are identified, considering associations with multiple possible etiologies; and - enhance sampling and laboratory analytic methods to improve assessment of environmental exposures to molds and fungi (5). In response to the reviewers' recommendations, CDC staff developed a plan to conduct surveillance for AIPH, investigate clusters of cases, and conduct studies. In formulating this response, CDC convened three meetings to establish a case definition and classification scheme for public health surveillance for AIPH, recommend a standard home environmental investigation protocol, and outline a plan for surveillance and investigation of AIPH among infants. As a consequence of these meetings, CDC has determined that a series of surveillance activities should be initiated to direct future efforts. In addition to providing an overview of the results of the three meetings, this report describes surveillance activities and how results from those activities can guide efforts to investigate the burden and etiology of AIPH among infants.
AIPH among infants is a diagnosis of exclusion. Certain syndromes (Box 1) and other disease states can occur with pulmonary hemorrhage. Thus, differential diagnoses and neonatal medical problems that can cause pulmonary hemorrhage should be ruled out.

# Meeting Panelists and Goals
Three meetings of panelists were convened to advise CDC staff regarding investigation of AIPH among infants. The Case Definition Panel included three pediatric pulmonologists, one pediatric intensive care specialist, one pediatric pathologist, two epidemiologists, and one environmental epidemiologist. The purpose of this panel was to recommend a case definition for use in public health surveillance for AIPH to facilitate case finding. Case finding will facilitate documentation of the burden of the condition and identification of possible etiologic agents or risk factors.
The Surveillance Implementation Panel included one pediatrician, one pediatric pulmonologist, one forensic pathologist, three epidemiologists (including one state epidemiologist), and four environmental epidemiologists (including one state epidemiologist and one toxicologist). Its purpose was to recommend a standard approach for public health surveillance for AIPH.
The Home/Indoor Environment and Laboratory Investigation Panel included two mycologists, one biochemist, two microbiologists, two industrial hygienists, two toxicologists, and one environmental epidemiologist. Its purpose was to recommend standard approaches and protocols for environmental data collection, laboratory analysis, and data interpretation during public health surveillance for AIPH.
For each of the three areas, group discussion led by a moderator was based on prepared questions. Participants produced written summaries, which form the basis of the recommendations provided in this report.

# BOX 1. Pulmonary hemorrhage terminology
The term used for the cluster of cases reported in Cleveland- was pediatric idiopathic pulmonary hemorrhage and hemosiderosis. The term pulmonary hemorrhage has been used to describe situations with identifiable causes of bleeding.  Idiopathic pulmonary hemosiderosis (IPH)  or primary hemosiderosis  has been used to denote presumably idiopathic bleeds or the accumulation of iron as hemosiderin.  The terms pulmonary hemorrhage and primary hemosiderosis are often used interchangeably. The new International Classification of Diseases, Tenth Revision (ICD-10) mortality coding system   has no code for idiopathic pulmonary hemosiderosis. The CDC definition of a case of AIPH in an infant uses the term pulmonary hemosid-erosis as a pathological finding to denote the possible occurrence of pulmonary hemorrhage, and not to describe a clinical syndrome.
The term pulmonary hemorrhage encompasses multiple clinical syndromes, including - diffuse pulmonary hemorrhage;   - pulmonary hemorrhage of the newborn (ICD-9: 770.3; ICD-10: P26)   or hemoptysis; - cough with hemorrhage; - pulmonary hemorrhage not otherwise specified  786.3; ICD-10 R04, R04.2); and - idiopathic pulmonary hemosiderosis (ICD-9: 516.1, no ICD-10 code).

# Case Definition Case Classification and Severity Criteria
AIPH is the sudden onset of pulmonary hemorrhage in a previously healthy infant in whom differential diagnoses and neonatal medical problems that might cause pulmonary hemorrhage have been ruled out. Pulmonary hemorrhage can appear as hemoptysis or blood in the nose or airway with no evidence of upper respiratory or gastrointestinal bleeding. Patients have acute, severe respiratory distress or failure, requiring mechanical ventilation and chest radiograph (CXR), and usually demonstrate bilateral infiltrates.
AIPH among infants and sudden infant death syndrome (SIDS) potentially share similar risk factors (e.g., age group and maternal cigarette smoking). Also, in certain cases, SIDS is associated with pulmonary hemorrhage found at autopsy (6,7). Thus, factors that are known risk factors for SIDS should be identified when evaluating an infant possibly having AIPH. Potential information sources for case-identification and casestatus classification during an investigation of pulmonary hemorrhage are provided (Table 1).

# Clinically Confirmed Cases of AIPH Among Infants
Criteria for a confirmed case include pulmonary hemorrhage in a previously healthy infant aged 32 weeks, with no history of neonatal medical problems that might cause pulmonary hemorrhage, and whose condition meets all of the following three criteria:
- Abrupt or sudden onset of overt bleeding or obvious evidence of blood in the airway, including -epistaxis, hemoptysis, or frank blood in the airway below the larynx at visualization, not caused by any medical procedure (e.g., laryngoscopy or intubation); or -identification of hemosiderin-laden macrophages (>20% of pulmonary macrophages containing hemosiderin on bronchoalveolar lavage or biopsy specimen).
A source of bleeding from the nose and oropharynx should be ruled out at the time of admission. - Severe-appearing illness leading to acute respiratory distress or respiratory failure, resulting in hospitalization in a pediatric intensive care unit (PICU) or neonatal intensive care unit (NICU) with intubation and mechanical ventilation. - Diffuse unilateral or bilateral pulmonary infiltrates visible on CXR or computerized tomography (CT) of the chest. CXR or chest CT findings should be documented within 48 hours of examination of the infant. A previously healthy infant should
- have been discharged from the hospital after birth with an uneventful course before the occurrence of bronchoalveolar hemorrhage; - never have been previously intubated, nor required respiratory support with oxygen; - not have evidence of physical abuse;
- not have any abnormality identified on admission or follow-up bronchoscopy that would explain the bleeding; and - not have neonatal medical problems that can cause pulmonary hemorrhage. CDC will adhere closely to this case definition, requiring that all the criteria be met for a confirmed case. The definition for a clinically confirmed case excludes pulmonary hemorrhage among older children and infants with restricted access to a PICU. Because no criteria exist for postmortem examinations, this definition excludes infants who die before hospital and PICU admission, whose illness might have met the case definition. However, the definitions for probable and suspect cases (see the following) will capture the majority of these cases and allow identification of illness among infants who die before examination by a physician.

# Probable Cases of AIPH Among Infants
Criteria for a probable case include a previously healthy infant aged 32 weeks,
- who has a sudden onset of bleeding from the airway, with or without respiratory distress, with or without intubation, and with or without pulmonary infiltrates on CXR or chest CT; or - who died and had evidence of bleeding from the airway found on autopsy or postmortem; had been in respiratory distress; would or should have been intubated in the opinion of a clinician; and would have had infiltrates on CXR or chest CT.

# Suspected Cases of AIPH Among Infants
Criteria for a suspected case include a previously healthy infant,
- who died and had evidence of bleeding from the airway found on autopsy or postmortem or who - either did not have chest imaging studies or had imaging studies that indicated no pulmonary infiltrates. Respiratory distress or intubation is not required for a suspected case.

# Severity Classification Scheme for AIPH Among Infants
Because of the potential for variation in symptoms among infants for each of the criteria, different case combinations might be related to the timing or duration of symptoms, disease severity, pathologic processes, or etiologic agents associated with AIPH among infants. A discussion of the proposed case-classification categories for AIPH among infants is provided (Tables 2 and 3).

# Discussion
- Bleeding might begin in a localized region of one lung with dispersion of blood to other areas of the lung through the airways - Initial chest radiograph (CXR) might indicate unilateral infiltrates, but following dispersion indicates diffuse infiltrates - Infants with unilateral infiltrates are considered confirmed for AIPH, but their characteristics might be different from infants with diffuse infiltrates
- Not considered confirmed because identification depends on lavage or biopsy finding of hemosiderin-laden macrophages and not on active bleeding or recovering blood from below the larynx - Work of breathing might vary for infants with a similar pathology (e.g., resulting from different body temperature, serum glucose levels, and duration of respiratory distress) - Infants who do not need intubation would not have acute bleeding directly identified from below the glottis - Upon initial examination, infants' circumstances might vary; information should be collected to identify these circumstances as best as possible during data abstraction so that the categories can be expanded if needed during data analysis - The circumstances might be that 1) the attending physician intended to intubate an infant who died; 2) the clinician who reviewed the death of an infant with postmortem findings consistent with pulmonary hemorrhage secondary to clinical respiratory failure thought the infant should have been intubated; 3) the infant died before arrival at the hospital and therefore was not intubated nor received thoracic imaging studies - Age-specific normochromic, normocytic, or microangiopathic anemia might indicate different pathophysiologic processes and in conjunction with appropriate clinical signs and symptoms might be supportive of a diagnosis of AIPH - Rankings of 1-5 represent categories with decreasing levels of certainty; 1 = highly probable, and 5 = least probable. The letter designations a, b, and c represent approximately equivalent levels within each category (see also Table 2).

# MMWR March 12, 2004
A summary of clinical features of AIPH among infants (Table 4) (Box 2) and neonatal medical problems and differential diagnoses that should be ruled out before classifying a case as AIPH among infants (Box 3) are included. Other differential diagnoses associated with pulmonary hemorrhage are listed (Table 5).

# Feasibility Study To Determine the Concordance of ICD Codes for Pulmonary Hemorrhage with the CDC Case Definition
Prospective nationwide surveillance for cases of AIPH among infants is difficult to justify on the basis of the available epidemiologic data. In addition to the limitations reported for the Cleveland study (5), no risk factors were conclusively linked to disease in the Chicago investigation ( 4), and only one other cluster (in Detroit) was reported during 1992-1996 (7).
CDC will retrospectively review cases of pulmonary hemorrhage to determine the public health impact of AIPH among infants and to generate hypotheses regarding the importance of risk factors possibly associated with AIPH among infants. If that review indicates that AIPH among infants is a separate clinical entity and that these cases have occurred in clusters, or that an increase in incidence or mortality is associated with these cases, CDC will initiate prospective surveillance and case ascertainment to identify cases for epidemiologic studies designed to confirm or disprove associations between pulmonary hemorrhage host factors, environmental factors, and biologic agents, including such molds as S. chartarum (5).

# Retrospective Review by Using Existing Data Sources
The ability to use existing data sources should substantially facilitate both determining the public health impact of AIPH among infants. However, the reliable data regarding mortality from pulmonary hemorrhage is only available at the national level. CDC conducted a preliminary evaluation of ICD codes for surveillance of pulmonary hemorrhage among infants to determine whether existing data sources can be used to estimate the magnitude of the problem of AIPH among infants. CDC examined data from the National Hospital Discharge Survey (NHDS) and National Mortality Data. Possible cases of AIPH among infants were identified by using ICD-9 codes 770. 3, 784.7, 784.8, 786.3, and 516.1 (Table 6).
Infants identified by ICD-9 codes 770.3 and 786.3 differ from the cases reported in Cleveland. In the national datasets, the majority of cases of pulmonary hemorrhage had diagnoses such as prematurity or immaturity and death occurring within the first 7 days of life. The Cleveland cases occurred among stable, healthy, mature infants who had been discharged from the hospital to their homes after birth and subsequently experienced pulmonary hemorrhage (8)(9)(10). Thus, the estimates of deaths and hospital admissions for cases of pulmonary hemorrhage using ICD codes 770.3 and 786.3 does not distinctly identify infants with AIPH as defined by CDC. In addition, these national datasets do not determine if infants had identifiable etiologies or complications before their discharge from the hospital or their death. Because the estimated number of hospitalized cases with a primary diagnosis of pulmonary hemorrhage was less than the number of deaths, these national datasets might not be reliable for surveillance for infantile pulmonary hemorrhage. These analyses might be better performed by using state-based data.
A retrospective review for AIPH among infants will be performed in metropolitan cities in those states with the highest death rates and with >100 deaths associated with pulmonary hemorrhage among infants, on the basis of relevant ICD-9 and ICD-10 codes used from 1979 to the most recent available data. By focusing on PICUs and NICUs with substantial numbers of deaths, cases from innercity catchment areas, where the incidence of AIPH among infants is suspected to be higher, will be captured. Potential cases will be identified by using standardized methods of case ascertainment and data collection from hospital discharge and mortality data sources, based on ICD codes. Potential cases will be compared with the recommended case definition by reviewing medical records related to all cases of pulmonary hemorrhage observed since 1979 among children aged <2 years.
This retrospective review of AIPH among infants will - determine whether AIPH among infants is a distinct clinical entity within existing ICD-9/ICD-10 diagnostic codes for pulmonary hemorrhage; - describe the epidemiology of pulmonary hemorrhage; - identify trends in the frequency of cases and the geographic distribution and clustering of cases; - estimate the public health impact of AIPH among infants;
- identify groups at high risk for AIPH among infants; and - determine the need for prospective surveillance as a source of cases for a case-control study. The data will be reviewed to determine how these cases, including the apparent case clusters of AIPH among infants in Cleveland and Chicago, have been coded on hospital discharge abstracts, and how deaths attributed to the syndrome have been characterized on death certificates. Both Ohio and Illinois meet the criteria of >100 deaths from pulmonary hemorrhage. In Cleveland and Chicago, this review also will

# TABLE 4. Clinical features of acute idiopathic pulmonary hemorrhage (AIPH) among infants Finding
No evidence of cow milk protein allergy or associated respiratory, heart, kidney, or pancreatic disease- Abrupt cessation of crying or unusual crying or irritability hours to days before the initial recognition of blood in the airway  Not observed  Decreased muscle tone and dusky pallor minutes to hours before progressing to sudden onset of hypoxemic respiratory distress or failure  Hours to days before onset of respiratory failure Accompanies or immediately precedes respiratory failure   Acute and appears to be idiopathic   Characterized by tachypnea, grunting, and chest retractions   Diffusely diminished breath sounds without the presence of rales or rhonchi* Often requires intubation and mechanical ventilation; intubation when required is for 2-7 days    Often demonstrates bilateral pulmonary infiltrates within the first 24 hours    Typically, alveolar infiltrates begin to clear within the first 24-48 hours    Atraumatic intubation; bronchoscopy including inspection of upper airway Typically, no source from the lung or gastrointestinal tract; presumed to be from diffuse alveolar capillary injury     Typically, found in bronchoalveolar lavage fluid; might not be present in an infant experiencing an acute, initial pulmonary bleed     Indicates evidence of bleeding into the lungs; finding >20% of total pulmonary macrophages containing hemosiderin can be consistent with pulmonary hemorrhage that occurred >48 hours before examination     First 48 hours, fragmented or damaged red blood cells, hemoglobinuria; microangiopathic anemia might be indicative of a hemolytic process; normochromic normocytic might be consistent with acute, abrupt blood loss* Serum negative for antiglomerular basement membrane antibody, anticytoplasmic neutrophilic antibody, complement titers, serum immune complexes, and antinuclear antibody      None; spontaneous recovery with or without supportive care indicates these pathophysiologic processes are not the cause of bleeding

# BOX 2. Clinical descriptions of pulmonary hemorrhage
In early texts, pulmonary hemorrhage was not commonly described in children, although it was noted to occur.- Blood found in the airways or alveoli of humans can result from different anatomic sites. Specific sites can include alveoli, large or small conducting airways, or the nasopharynx and gastrointestinal tract with pulmonary aspiration. Regardless of the origin of blood entering the lung, substantial amounts of blood lead to impaired gas exchange, altered pulmonary mechanics, and respiratory distress. Different pathophysiologic processes are associated with pulmonary hemorrhage. These can be divided into - conditions where bleeding occurs at sites of normal tissue with mechanical disruption causing a loss of vascular integrity (e.g., intentional suffocation and mitral valve disease); - vascular inflammation, whereby the inflammatory process causes a loss of vascular integrity (e.g., vasculitis secondary to such conditions as collagen vascular diseases); - vascular malformations, whereby a combination of altered vascular integrity and physical influences (e.g., Laplace's law  ) lead to disruption of the blood vessel; and - coagulopathies, which usually also require additional physical disruption of the blood vessel through greater than normal transpulmonary vascular pressures.
The manifestations of pulmonary hemorrhage can be classified into different syndromes. Diffuse pulmonary hemorrhage is usually diagnosed by bronchoscopy, either by virtue of grossly bloody lavage fluid or by the presence of hemosiderin-laden macrophages in bronchoalveolar lavage. In biopsy and autopsy tissue, the diagnosis is made on the basis of the presence of recent blood and hemosiderin in the alveolar spaces or the interstitium.  In the immunocompromised host, intra-alveolar bleeding can result from thrombocytopenia often associated with other factors. Diffuse pulmonary hemorrhage (DPH) can either be secondary to other disease states, associated with other organ dysfunction, or be isolated. Isolated causes of DPH include lung immaturity, cow milk hypersensitivity, pulmonary capillary hemangiomatosis, and idiopathic causes.  Pulmonary hemorrhage of the newborn (ICD-9: 770.3; ICD-10: P26) is manifested by focal hemorrhage into airspaces or the interstitium in the lungs of infants with hyaline membrane disease, bronchopulmonary dysplasia, and other neonatal pulmonary disorders. These infants are most often male, preterm, small for gestational age, and have a history of perinatal stress.   The etiology and pathogenesis of the disorder has not been elucidated.
Hemoptysis, cough with hemorrhage, pulmonary hemorrhage not otherwise specified (ICD-9: 786.3; ICD-10 R04, R04.2) is an acute manifestation of bleeding from the airway. This ICD category captures all the nonneonatal (and certain neonatal) diagnoses of pulmonary hemorrhage. Children with pulmonary hemorrhage might not appear to have hemoptysis if they swallow their sputum.
Consensus is lacking on the meaning of the term idiopathic pulmonary hemosiderosis (ICD-9: 516.1, no ICD-10 code). One pathology text states that the term denotes a separate clinical entity of which diffuse pulmonary hemorrhage is the major manifestation.   A later edition of the same text   notes that the presence of hemosiderin in lung macrophages indicates degradation products of hemoglobin. Hemosiderin is thus a pathologic state indicative of bleeding of any type into the lungs* secondary to the processing of hemoglobin in the red blood cells in the airway by alveolar macrophages.    Adults with active alveolar hemorrhage have high hemosiderin scores in bronchoalveolar lavage fluid,    but hemosiderin-containing macrophages have limited differential diagnostic value.    In one clinical text, the term means diffuse recurrent intrapulmonary hemorrhage that is not secondary to bleeding from trauma, bleeding from the airways, tumors, or left ventricular failure. Another author     describes variants of primary and secondary pulmonary hemosiderosis.
On review of National Hospital Discharge Survey data for 1979-1996 and national mortality data for 1979-1998 for ICD-9 code 516.1 for infants, no instances were found in either dataset where ICD-9 code 516.1 was the primary listed diagnosis. However, in 207 cases, this code was the other listed diagnosis. This indicates that idiopathic pulmonary hemorrhage is usually an accompanying diagnosis to other diagnoses that result in hospitalization or death among infants. If performed, environmental assessment of the home to gather pertinent risk-assessment data should use standard protocols designed by trained environmental health professionals. At a minimum, the assessment should involve visual inspection, including checks for dampness, water damage, obvious mold, evidence of pests, and environmental tobacco smoke. Depending on the assessed need for further evaluation and the resources available, additional investigation might include determining moisture content, settled dust sampling, air sampling for different allergens, and biologically active compounds, and other investigations as needed.

# Conclusion
CDC recommends a definition for a clinically confirmed case of AIPH among infants on the basis of 1) evidence of blood in the airway; 2.) age <1 year; 3) absence of medical conditions related to pulmonary hemorrhage; and 4) severe acute respiratory distress or respiratory failure, requiring admission to a PICU with intubation and mechanical ventilation. CDC recommends that PICUs report cases that meet the CDC case definition to state health departments and to CDC.
CDC will retrospectively analyze state-level mortality and hospitalization data based on ICD codes and will retrospec-  tively review discharges for pulmonary hemorrhage in selected PICUs. These studies will - distinguish between the clinical findings associated with different symptoms of AIPH among infants; - determine whether ICD codes capture cases that meet the CDC-recommended case definition for AIPH among infants; - determine whether AIPH among infants is a distinct recognizable clinical entity; - determine the proportion of cases ascertained retrospectively through ICD-9 codes that meet the clinical case definition by estimating PPV of ICD-coded data; and - define the magnitude of AIPH among infants and the need for conducting etiologic studies. CDC will review the Cleveland and Chicago case series to determine the degree to which the present case definition applies to them. In addition, CDC will evaluate the present case definition on the basis of data from initial surveillance findings and modify it as appropriate.
If these reviews establish that AIPH among infants is a public health problem on the basis of increasing numbers or clusters of cases geographically or temporally, targeted prospective case surveillance will be initiated. If prospective surveillance is initiated, CDC will maintain a database of current cases of AIPH among infants, reported by PICUs that meet the case definition. The database will serve as a source of cases for casecontrol studies to determine etiology. CDC will work with state and local health departments to investigate clusters of AIPH among infants cases. ('tr st-"w r-the) e e