SICKLE CELL DISEASE WITH COMPLICATED INFLUENZA B VIRUS INFECTION Ernest A. Turner, MD, Harold D. Thompson, MD, Churku M. Reddy, MD, Mary Ann South, MD, Brenda R. Garrett-Ellis, MD, and Radmila R. Mirkovic, MD Nashville, Tennessee

The Committee on Infectious Diseases of the American Academy of Pediatrics, and the Advisory Committee on Immunization Practices of the Center for Disease Control for many years have recommended the routine use of influenza vaccine in various hemoglobinopathies including sickle cell disease.1'2 This recommendation, however, has not been included in the patient care protocols of the Comprehensive Sickle Cell Centers program of NIHLB.3 Most clinicians have not used yearly influenza vaccine for their patients with sickle cell disease. This article reports a case of a 5-year-old boy with sickle cell disease who had not received influenza vaccine. He developed pneumonitis and acute myositis during a serologically confirmed influenza B virus infection. The incapacitating and protracted course of his illness presented diagnostic and management problems. His case strongly supports the recommendation of the two infectious disease committees. (J Nati Med Assoc. 1992;84:524-527.) Key words * sickle cell disease * influenza infection

It has been well recognized that patients with sickle cell disease are at increased risk for serious infections with certain bacterial agents. Except for parvovirus B 19, such an increased morbidity has thus far not been established for viral infections, including influenza A and B. Influenza B infection can produce a variety of severe clinical conditions, pulmonary complications being the most frequent ones.4-8 These complications, unlike those caused by the influenza A virus, have not been recognized as occurring more frequently in so-called high-risk groups.4 The authors' literature search failed to reveal any published data on patients with sickle cell disease who also had complicated influenza A or influenza B infections, but the authors recently have observed such a case. A 5-year-old boy with sickle cell disease, who was admitted for leg pain and fever, developed a protracted course that proved to be caused by influenza B infection. This case report points out the need to do diagnostic studies of illnesses that possibly could be triggered by influenza infection, because there can be an atypical presentation of influenza in sickle cell disease. In addition, because the risk levels for influenza-related complications in sickle cell disease have not yet been established, these complications should be reported to the Comprehensive Sickle Cell Centers program.

CASE REPORT From the Department of Pediatrics, Department of Radiology, and Comprehensive Sickle Cell Center, Meharry Medical College, Nashville, Tennessee. This study was supported by grants from the NIH, USPH P60-HL38737 and GM 08198. Requests for reprints should be addressed to Dr Ernest A. Turner, Comprehensive Sickle Cell Center, Meharry Medical College, 1005 D.B. Todd Blvd, Nashville, TN 37208. 524

A 5-year-old black boy with sickle cell disease presented to the emergency room because of pain in both legs. He had a history of fever for 2 days prior to admission and was anorexic. Upon admission, the patient's vital signs were: temperature-36.9° C, respiratory rate-32 breaths per JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 84, NO. 6


Figure 1. Admission chest radiograph. There is a mild increase in interstitial densities in hilar and basilar areas.

Figure 2. Chest radiograph-fifth hospital day. There is a marked progression of the bibasilar patchy densities, and atelectasis has occurred.

minute, pulse-88 beats per minute, and blood pressure120/80 mm Hg. The boy was alert and in no acute distress, but was uncomfortable because of leg pain. He weighed 15 kg (5th percentile), and his height was 106 cm (25th percentile). His chest was clear to percussion and auscultation. He showed some guarding and reported generalized tenderness in both legs. The remainder of his physical examination was unremarkable. The initial laboratory studies revealed a white blood cell count of 21 000/mm3, with 48% neutrophils, 9% bands, 39% lymphocytes, and 4% monocytes. His red blood cell count was 2.29 X 106/mm3, hemoglobin 7.2 g/dL, hematocrit 20.8%, and reticulocytes 13%. Electrolyte values were within normal limits, and urinalysis was normal. Blood and throat cultures, taken in the emergency room, remained negative. His admission chest radiograph (Figure 1) showed a mild increase of interstitial densities primarily in hilar and basilar areas. The patient received intravenous hydration and intravenous ampicillin 100 mg/kg/day. Because he was still complaining of pain in his legs, Demerol was started at a dose of 25 mg by mouth every 4 hours. From the second hospital day the patient's temperature started spiking intermittently and reached its highest point of 40.10 C on the fourth hospital day. At that time he began to have a nonproductive cough and nasal flaring. Another chest radiograph was taken and revealed definite bibasilar patchy infiltrates with some segmental atelectasis. The overall impression was that of a bibasilar pneumonitis with associated atelectasis. Ampicillin was replaced by cefuroxime, 100 mg/kg/ day, intravenously. On the fifth hospital day, the boy's cough became productive and rhonchi became audible

bilaterally. Sputum, as well as repeated throat swab and blood, were obtained for culture; no pathogenic bacteria grew. Cold hemagglutinin titer was negative. The repeated chest radiograph (Figure 2) revealed a marked progression of the bibasilar patchy densities when compared with the one taken 24 hours earlier. The first blood sample for respiratory viral titers was procured at that time (Table). From the sixth to the ninth hospital days the patient's temperature ranged up to 38.30 C. Cefuroxime was discontinued because it was felt that the prolonged elevated temperature might be a drug fever caused by the antibiotics. He was transfused with 140 cc of packed red blood cells. During this entire 9-day period, the patient refused to get out of bed and walk. His complaint was that he could not stand on his legs. However, despite the fever and quite impressive radiological finding, the boy was never in respiratory distress. Symptoms of hypoxia, dyspnea, or cyanosis were never apparent, and his nasal flaring was transient, having lasted only 1 day. On the 10th hospital day the patient's temperature suddenly dropped to 37.20 C. He started walking on his own, and his appetite returned. On auscultation, the chest was nearly clear, but he still continued to have a productive cough. The purified protein derivative test was negative on final reading. The radiograph showed residual interstitial densities with resolution of the atelectatic areas (Figure 3). On the 12th hospital day his second blood sample for respiratory viral titers was obtained, and he was discharged with the diagnosis of vaso-occlusive crisis and resolving pneumonitis of unknown etiology.






Hospital Day

Day After Onset

Influenza A

Influenza B

5 12

7 14

< 1:8 < 1:8

1:1024 1:512

Respiratory Para-lnfluenza Para-lnfluenza Adenovirus Syncytial Virus Virus Type 2 Virus Type 3

1:32 1:32

1:8 1:8

1:16 1:16



Mycoplasma Pneumoniae

1:16 1:16

*Tests performed at the Immunology Laboratory, Division of Laboratory Services, Tennessee Department of Health and Environment, Nashville, Tennessee. Influenza B complement fixing antibodies are expected to appear with the first symptoms and peak within 7 to 10 days after infection.

Figure 3. Chest radiograph-discharge. There are residual interstitial densities with resolution of the atelectatic areas.

When seen 3 weeks later, the boy was in good

condition, and had regained the weight lost during the illness. Shortly before he came for his follow-up visit, the results of serologic tests were received. The patient's two sera, collected on the seventh and 14th days of illness, had influenza B virus complement fixing (CF) antibodies at a titer of 1:1024 and 1:512, respectively (Table). Such high titers, even without documented seroconversion or virus isolation, indicate a true-positive recent influenza B infection.4 Therefore, the diagnosis of influenza B disease was made retrospectively. The authors' conclusion that the patient experienced influenza B pneumonitis and probably acute influenzal myositis was further supported by the negative blood, throat, and sputum cultures and other viral and mycoplasma serologic results.

DISCUSSION This case presents a complicated clinical course of 526

influenza B infection in a child with sickle cell disease. Although the disease in this patient was more incapacitating than life threatening, it posed two important problems. The first one was the diagnostic difficulty of differentiating the symptoms of vaso-occlusive crisis from those of an influenza infection per se. The next problem was the severe course of the disease, complicated by pneumonitis and possibly myositis, necessitating 12 days of hospitalization. The diagnosis of vaso-occlusive crisis is a frequent problem for physicians who care for patients with sickle cell disease because an objective diagnostic test is not available. On the other hand, myalgia is one of the more common symptoms during the acute phase of an influenza infection. The pain in these two conditions is so similar that in this patient influenza was not considered at all, and CPK (creatine phosphokinase) determinations that would have supported the presence of myositis were never done. Therefore, admission and discharge diagnosis was that of vaso-occlusive crisis. Even in retrospect it is not possible to decide if this patient experienced an episode of vaso-occlusive crisis precipitated by influenza B infection, or if the entire illness was caused by the infection. Only the protracted course and development of pneumonitis unresponsive to antibiotics suggested a viral infectious process in him. The authors found no reports in the literature of influenza-related complications in patients with sickle cell disease; this lack of reported cases may possibly be explained by misdiagnosis of influenzal illness as simple vaso-occlusive crisis or the acute chest syndrome, precipitated by an "undefined infection." The patient reported here had two complications of influenza, the common pneumonia and the unusual myositis. Pulmonary complications in the course of an influenza A or B infection may present in two forms. The first one is the primary influenzal pneumonia that JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 84, NO. 6


occurs early in the course of the disease and presents as an interstitial pneumonitis, as in our patient. The other type of pulmonary complication, the secondary bacterial pneumonia, develops later and causes a biphasic course of illness. The most common causative agents in this form of pneumonia are staphylococci, Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus pyogenes. The pathogenesis of this bacterial complication involves the initial degeneration and sloughing of mucus secreting and ciliated cells of the tracheobronchial lining, caused by the influenza virus. The denuded airway surface then becomes susceptible to bacterial invasion.9 Patients with sickle cell disease share an additional risk if these pathogens are given access to their blood, since they may develop fulminant sepsis caused by S pneumoniae or H influenzae. Acute influenzal myositis presented classically in this patient. The clinical manifestations appear early in the disease, and the leg pain is often so severe that many children, like this patient, refuse to walk.6 This young patient might have been spared his lengthy and painful infection if he had been given prophylaxis with the available influenza vaccine, which is safe, effective, and well tolerated. Routine use of the influenza vaccine in sickle cell disease and other chronic hemoglobinopathies has been recommended by both the Committee on Infectious Diseases of the American Academy of Pediatrics,' and the Advisory Committee on Immunization Practices of the Center for Disease Control.2 This case, even as a single example of diagnostic difficulty, calls for improvement of influenza vaccination practices in sickle cell disease. However, it does not permit the generalization that influenza usually runs a severe and complicated course


in patients with sickle cell disease. Only a prospective study of patients with sickle cell disease and suspected influenza A or B infection, undoubtedly best attempted by cooperative efforts of all Comprehensive Sickle Cell Centers, will show whether sickle cell disease patients are indeed at increased risk for influenza-related complications. Acknowledgment The authors thank Natalie W. Shye, Helen J. Robinson, and Charlotte J. Nicholson for their editorial assistance.

Literature Cited 1. American Academy of Pediatrics. Report of the Committee on Infectious Diseases. 20th ed. Elk Grove Village, III: American Academy of Pediatrics; 1986:41. 2. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Prevention and control of influenza:

Part I, Vaccines. MMWR. 1989;38:305. 3. US Department of Health and Human Services, Public Health Service, National Institutes of Health. Management and Therapy of Sickle Cell Disease. Washington, DC: Government Printing Office; 1991. NIH publication 91-2117. 4. Baine WB, Luby JP, Martin SM. Severe illness with influenza B. Am J Med. 1980;68:181-189. 5. Connor E, Powell K. Fulminant pneumonia caused by concomitant infection with influenza B virus and Staphylococcus aureus. J Pediatr 1985;1 06:447-450. 6. Dietzman DE, Schaller JG, Ray CG, Reed ME. Acute myositis associated with influenza B infection. Pediatrics. 1 976;57:255-258. 7. Glezen WP, Payne AA, Synder DM, Downs TD. Mortality and influenza. J Infect Dis. 1982;146:313-321. 8. Nolan TF, Goodman RA, Hinman AR, Noble GR, Kendal AP, Thacker SB. Morbidity and mortality associated with influenza B in the United States, 1979-80: A report from the Centers for Disease Control. J Infect Dis. 1980;142:360-362. 9. Loosli CG. Influenza and the interaction of viruses and bacteria in respiratory infections. Medicine. 1973;52:369-384.


Sickle cell disease with complicated influenza B virus infection.

The Committee on Infectious Diseases of the American Academy of Pediatrics, and the Advisory Committee on Immunization Practices of the Center for Dis...
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