Cardiopulmonary Manifestations of Sickle Cell Disease in Childhood

By John A. Smith

C ARDIOPULMONARY manifestations due to sickle cell disease were initially reported

by Herrick’ in 19 10, who described a young man with peculiar sickled-shaped cells and anemia. The patient suffered recurrent chills, fever, cough, shortness of breath, and palpitations; car- diac enlargement, a murmur, and numerous moist rales were found on physical examination. In subsequent publications concerning sickle cell disease, it was noted that both cardiac and pulmonary changes played a significant role in the clinical complications and long-term outlook of the disease.’

In most large series of children with sickle cell disease, the heart and lungs appear involved at a very young age.3-s Reynolds6 pointed out that radiologic changes involving the heart and lungs are seen in young children. A description of “sickle cell lung” is offered in several articles.6,7 Cardiomegaly and pneumonia are the most com- mon thoracic findings clinically and at autopsy in all age groups.

CARDIAC MANIFESTATIONS

Varat et al8 showed that anemia of any kind may cause increased cardiac output, even at rest. This results in increased stroke volume and work- load, primarily of the left ventricle. To further compensate for the reduced oxygen-carrying capacity of blood, peripheral blood flow is raised by vasodilatation, thereby improving tissue extraction of oxygen. Clinically, anemic patients have cardiac murmurs, primarily as a result of increased blood flow through cardiac chambers and across valves.8 ECG findings are not charac- teristic. Radiographically, the heart is usually enlarged with severe anemia, but usually the size

From the Department of Radiology, Riley Hospital for Children, Indiana University School of Medicine.

John A. Smith: Professor of Radiology. Address reprint requests to John A. Smith, Md, Depart-

ment of Radiology, Riley Hospital for Children, Indiana University School of Medicine, 702 Barnhill Dr, Indianapo- lis, IN 46.223.

0 1987 by Grune & Stratton, Inc. 0037-I 98X/87/2203-0005$05.00/0

returns to normal after correction of the anemia. In sickle cell disease, the cardiac enlargement does not regress when the anemia is corrected. Other differences in sickle cell disease patients are thought due to a combination of such factors as chronic anemia, increased blood viscosity, and microthrombi.

Cardiomegaly

Children with sickle cell disease develop chamber enlargement and increased left ventric- ular mass at a relatively early age, and these findings increase with age. In one large series, cardiomegaly was noted in 80%. Klinefelter3 found cardiomegaly in all 12 of his patients between the ages of 8 and 27 years. It has been noted that the cardiac configuration and the murmurs often led to a mistaken diagnosis of rheumatic heart disease.“”

Radiologic Appearance

Most investigators, notably Reynolds,6 have described the heart as enlarged and the contour nonspecific. The heart is frequently globular in shape (Fig 1). A left ventricular configuration (Fig 2) or right ventricular prominence, with enlargement of the pulmonary conus is occasion- ally described.” Prominence of the pulmonary conus has not been a distinctive feature in the pediatric age group. In general, the contour of the heart suggests no specific chamber enlarge- ment. During aplastic crisis, the heart may fur- ther dilate and the pulmonary vessels become engorged. The heart usually returns to its former size following resolution of the crisis.

Two predominant theories concerning the development of cardiac enlargement have been popularized. First, there is cardiac dilatation and increase in the left ventricular mass as a result of the increased how through the heart secondary to the chronic anemia. Second, the sickling pro- cess may effect the myocardium itself by produc- ing microinfarcts or anoxia due to flow abnor- malities in the small vessels supplying the myo- cardium.12 Thus, there are areas of fibrosis within the myocardium producing a picture that

160 Seminars in Roenrgenology, Vol XXII, No 3 (July), 1987: pp 160-167

CARDIOPULMONARY MANIFESTATIONS OF SICKLE CELL 161

Fig 1. A lo-year-old boy with nonspecific heart murmur. The chest radiograph shows a globular shaped enlargement of the heart.

suggests myocardiopathy. This latter effect has not been completely substantiated at autopsy.

Cardiac Dysfunction

Although sickle cell disease has been thought to be associated with cardiac dysfunction, there

is little evidence to support this view.‘* When various left ventricular function studies are com- pared, most of the abnormal parameters relate to volume overload, attributable to the anemia as described earlier, and not to chamber dysfunc- tion as a result of sickle cell disease.

Fig 2. A 12-year-old boy with cardiac murmur. The chest radiograph shows a long straight left heart border, suggesting left ventricular hypertrophy.

162 JOHN A. SMITH

In one series, 18% of the patients showed left ventricular hypertrophy, while only 6.7% had evidence of right ventricular hypertrophy on ECG.’ Likewise, multiple gated radionuclide imaging has failed to demonstrate significant chamber dysfunction related to sickle cell disease (Fig 3). In other studies using echocardiography, an increased left ventricular end-diastolic dimen- sion along with depressed levels of performance, was demonstrated in symptomatic children. This depression was thought to be related to the severity of anemia, and returned to normal with correction of the anemia.13

Congestive heart failure as a result of dysfunc- tion of the heart in children has been likewise difficult to prove. Most cardiac catheterization studies in asymptomatic patients have demon- strated normal right heart pressure with rela- tively low pulmonary vascular resistance at

rest.14 In acutely ill patients, pulmonary venous engorgement may be seen on radiographs. Some develop alveolar and interstitial infiltrates, called “sickle cell lung disease” (Fig 4), with the appearance of pulmonary edema. The cause of this pattern may be pneumonitis, vaso-occlusion related to sickling and to marrow emboli, or overhydration as a result of vigorous fluid man- agement during the treatment of crisis.”

Postmortem study reveals dilatation of both right and left ventricles in children. A few patients have shown evidence of myocarditis. Abnormalities of the mitral valve are occasion- ally found. Death in a child attributable to car pulmonale or intractable right heart failure is rare.16-‘* Autopsies on two pregnant women with sickle cell anemia revealed only left ventricular hypertrophy and congestive failure, suggesting acute left ventricular dysfunction. Coronary arteries were normal at autopsy in all children examined.

PULMONARY MANIFESTATIONS

Acute Pulmonary Infection

In a large series of cases of sickle cell disease, pulmonary disease was the most common reason for hospitalization. I9 There were 12 proven cases of bacterial pneumonia, 72 cases of presumptive bacterial infection (based on nasopharyngeal, blood, or stool cultures), and 85 cases where no diagnosis was rendered. Pneumonia was two to five times more common in patients 3 years of age or less. Of all patients with pneumonia, 50% had already been hospitalized by age 3 with a previous bout of pneumonia. Thus, the age of the patient offers a valuable clue to help differentiate cases of pneumonia from other pulmonary com- plications of the disease.”

Most pulmonary infections of proven cause are due to pneumococcus, although other organisms such as Mycoplasma pneumoniae, Hemophilus injluenzae, and Salmonella species occasionally cause pneumonia in young patients. Tuberculosis does not appear to be a major problem. Sickle cell disease patients seem to have difficulty in handling encapsulated bacteria.” Although no immunologic abnormality has been proven, pha- gocytosis of these bacteria appears impaired. The failure seems to occur in both the antibody response to certain bacteria, and in a breakdown of the secondary alternate complement pathway

Fig 3. A 13-year-old girl with prior history of a pulmo- nary infarct. Gated blood pool study shows normal left and right ventricles and evidence of mild mitral regurgitation.

CARDIOPULMONARY MANIFESTATIONS OF SICKLE CELL 163

Fig 4. A 12-year-old girl admit- ted in acute crisis with shortness of breath. (A) Radiograph of the cheat shows pulmonary vascular promi- nence with increased interstitial stranding. Sickle cell lung disease? Two days later, the patient devel- oped fever and cough. The chest radiograph (6) shows the pattern of pulmonary edema.

based on increased opsonin activity and phagocy- tosis.” Opsonins help tag bacteria for removal by other reticuloendothelial organ systems.

Lack of splenic function plays a role in the increased susceptibility to bacterial infection. Pulmonary macrophages may show decreased activity in an oxygen-poor environment and thus may be less effective in sickle cell disease patients. By the time children with sickle cell disease reach age 6, they have developed suffi- cient amounts of type-specific pneumococcal

antibody to protect themselves so that the inci- dence of severe pneumococcal infections de- creases markedly.

Radiologic Findings

The lungs appear to be involved in a lobar distribution. Frequently an upper lobe or middle lobe is involved (Fig 5).23 Lower lobe pneumonic infiltrates appear less common. They are usually confluent and alveolar in location. Occasionally, pleural effusion may accompany the acute infec-

164 JOHN A. SMITH

Fig 5. An 8-month-old infant with cough and fever associated with crisis. Pneumococcal pneumonia was established as the cause of the RUL and LUL infiltrate.

tion.24 Patchy infiltrate indicative of broncho- pneumonia occurs in about a third of patients with acute pulmonary infection (Fig 6).4 Myco- plasma pneumonia may involve the lower lobes bilaterally. Alveolar and interstitial infiltrates

along with pleural effusion are observed (Fig 7). Pneumonia in sickle cell disease patients tends

to resolve more slowly than in the general popu- lation. Furthermore, the chance of repeated infections appears greater in sickle cell disease.

Fig 6. A g-year-old with previous hospitalization for pneumonia, who now has cough and fever again. Patchy infiltrate in the left lower lung zone is seen on the radio- graph.

CARDIOPULMONARY MANIFESTATIONS OF SICKLE CELL 165

Fig 7. An g-year-old with purulent sputum secondary to mycoplasma pneumonia. Bilateral basilar infiltrate and pleural effusion are seen.

At autopsy, necrosis of the alveolar walls in areas of pneumonic infiltrate is frequently observed. This breakdown of the alveolar wall may account for the prolonged clinical course in these patients.4 Reactive lymphoid tissue has been observed in peribronchial lymph nodes in patho- logic specimens from infants and young chil- dren.” Previously, this hyperplasia was thought to be related to functional asplenism in sickle cell disease patients. Now it is believed that pulmo- nary infection plays a role in the development of the reactive lymphoid tissue.

Pulmonary Vascular Disease

Pulmonary thromboembolic events, including infarction, increase with age in sickle cell disease. During the early teens, it becomes increasingly difficult to separate pneumonia from pulmonary vaso-occlusive disease, because the clinical symp- toms at onset appear similar. Both may be her- alded by cough, chills, and fever, especially during a crisis.26 Pulmonary infarcts and throm- boembolism were found in one infant and three older children in one autopsy series.25 In general, when patients under age 5 exhibit cough, fever, and rales, pneumonia rather than thromboem- bolism is more likely, even though no bacterial organism can be demonstrated.

Pulmonary Thromboembolism

There are two mechanisms thought responsi- ble for pulmonary thromboembolism. The first is thrombosis due to intravascular sickling. Be- cause of the decrease in oxygen in the pulmonary vascular bed, there is increased sickling of red cells, accompanied by an increased blood viscosi- ty. The mechanical consequences of large num- bers of sickled red cells and slower flow are vascular statis and in situ formation of thrombi. This results in ischemic necrosis and even local fibrosis.” A further complication of the sickling process is physiologic shunting of blood around areas that are poorly ventilated, which further lowers the oxygen saturation of mixed venous blood, enhancing the sickling effects.

A second source of occlusion in the pulmonary vascular bed is marrow fat embolism. As a result of bone marrow necrosis during an aplastic crisis, particles of marrow and fat escape, enter the circulation, and lodge in the pulmonary vascular bed. Typically, the patient experiences severe bone pain followed by fever, shortness of breath, and lung infiltrates. 23 The two causes of throm- boembolism may be difficult to distinguish, since the clinical onset and the long-term consequences are similar.

Radiologic findings. There are few specific

JOHN A. SMITH

findings in the lungs in acute thromboembolism. Occasionally, there is pulmonary vascular engorgement with increased prominence of inter- stitial lines in the lung representing acute throm- boembolism. This may be the “sickle cell lung” described by Reynolds.6 Usually, there are no major areas of consolidation (Fig 8). This condi- tion has not been seen in young children, but does occur in teenage and older patients. Pulmonary emboli have been noted in autopsy in children of all ages, but few residual pathologic changes in the lungs of young children are related to these emboli. Both fat and sludged sickled red cells have been found to cause these emboli.

Pulmonary Infarction

Pulmonary infarction is likewise unusual in young children and is more common in teens and older individuals with sickle cell disease. The problems in differentiating pulmonary infarction from pneumonia have been difficult to resolve.’ The presence of purulent sputum, cough, and rales do not help to distinguish infarction from infection. Certainly age may be useful. If the patient is younger than 5 years, infection is favored. Location of infiltrates may be helpful.*’ Infection and infarction may coexist, since local necrosis from infarction may present a suitable environment for bacterial proliferation. In sickle cell crisis, the pulmonary changes are more likely

Fig 6. A 14-year-old boy with acute respiratory symp- toms accompanying a crisis. The chest radiograph shows bilateral perihilar infiltrates and pulmonary edema. The lungs were clear eight days later.

due to pulmonary infarction. Closely spaced repetitive episodes of acute pulmonary disease favor infarction.

Radiologic jindings. A clear radiograph at the onset of illness followed by an area of infil- trate suggests infarction. Infarcts occur most commonly in the lower lobes (Fig 9); the shape of

Fig 9. A 1 &year-old boy with left lower lobe pulmonary infarct (proven at autopsy). The chest radiograph shows a lesion in the left costophrenic angle.

CARDIOPULMONARY MANIFESTATIONS OF SICKLE CELL 167

the lesion appears to be of little value except when adjacent to a lateral pleural surface. Some investigators feel that a segmental distribution of infiltrate favors infarction. Radiologic resolution of an infarct is usually observed within seven to ten days, with no sequelae. Because most infarcts are self-limiting and resolve spontaneously, the added risk of pulmonary angiography is not deemed worthwhile in sickle cell disease. Radio- nuclide scanning is also of limited diagnostic value, because areas of infiltrate caused by either pneumonia or infarction will manifest perfusion abnormalities on scan.

The presence of blister cells on peripheral blood smear, lower lobe infiltrate on chest radio-

graph, history of repetitive chest symptoms or recent crisis in a patient of 12 or more years supports the diagnosis of pulmonary infarction.

In a few teenage patients, the lungs may show chronic pulmonary engorgement, a prominent azygos vein, evidence of congestive failure, and restrictive ventilatory defects, suggesting car pul- monale. This set of signs is related to chronic vaso-occlusive episodes in the pulmonary vascu- lar bed leading to pulmonary hypertension and right heart strain. Cor pulmonale in children is infrequent, but becomes more common later. One must consider this complication when there is deterioration of the cardiopulmonary system in an older patient.”

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