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Clinical and Laboratory Observations

A Case Series of Kawasaki Disease in Children With Sickle Cell Disease

Towerman, Alison S. RN, MSN, CPNP*,†; Reich, Patrick J. MD; Hulbert, Monica L. MD*

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Journal of Pediatric Hematology/Oncology: April 2022 - Volume 44 - Issue 3 - p 103-105
doi: 10.1097/MPH.0000000000002308
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Abstract

Sickle cell disease (SCD) is an inherited disorder characterized by hemoglobin (Hb) S in red blood cells (RBCs), leading to sickled RBCs that are more rigid and shorter-lived than normal RBCs. Vaso-occlusion and hemolytic anemia, with resulting ischemia and tissue damage, are disease hallmarks. The spleen produces antibodies and removes damaged cells and pathogens. In children with SCD, the spleen is damaged by sickled RBCs early in life. Impaired splenic function impedes the ability to mount immune responses to encapsulated organisms such as Streptococcus pneumoniae.1 The risk for septicemia and meningitis is high, necessitating prompt recognition and treatment of bacterial infections in febrile children with SCD.2 Evaluation must include a history and physical assessment, complete blood count with differential, reticulocyte count, and blood culture, with other studies obtained as indicated. Empiric parenteral antibiotics that provide coverage against S. pneumoniae and Gram-negative enteric organisms must be promptly administered.3

While bacterial infection is often appropriately suspected in febrile children with SCD, health care providers must consider alternative diagnoses in those with persistent fevers. Kawasaki disease (KD) is a multisystem vasculitis syndrome diagnosed by clinical criteria, which includes fever ≥38.3°C for at least 5 days plus 4 of the following clinical features: bilateral nonexudative conjunctival injection, classically limbic sparing; erythema of the oropharynx with red, cracked lips and “strawberry tongue”; edema or erythema to the hands and feet; polymorphous skin rash; and nonsuppurative unilateral cervical lymph node enlargement >1.5 cm in diameter.4,5 Additional nonspecific clinical features may be present, including uveitis, aseptic meningitis, urethritis, arthralgias, and arthritis.6 “Atypical” KD is defined as fever for at least 5 days, with 2 or 3 of the classic criteria, plus C-reactive protein ≥3.0 mg/dL and/or erythrocyte sedimentation rate ≥40 mm/h, and at least 3 supplemental laboratory criteria (Table 1).6

TABLE 1 - Final Laboratory Values Obtained From Patient 1 and Patient 2
Test (Normal Range) Patient 1 Patient 2
White blood count (5-15.5 k/cumm) 16.3* 10.7
Platelets (140-440 k/cumm) 734* 602*
Hemoglobin (11.5-13.5 g/dL) 7.9 9.6
Ferritin (7-140 ng/mL) 308 NA
Urinalysis Normal Normal
Erythrocyte sedimentation rate (0.0-20.0 mm/h) 122.0* 26.0
C-reactive protein (≤10.0 mg/L) 104.5* 11.6*
Lactate dehydrogenase (130-400 U/L) NA 1105
Albumin (3.2-5.0 g/dL) 3.6 3.4
Aspartate transaminase (10-60 U/L) 120 185
Alanine transaminase (10-40 U/L) 147* 24
*Laboratory results used to support KD diagnosis. Patients with >5 days of fever with 2 or 3 clinical criteria, C-reactive protein ≥3 mg/dL and/or erythrocyte sedimentation rate ≥40 mm/h with ≥3 of the following supplemental criteria meet diagnosis for atypical KD: (1) albumin ≤3.0 g/dL, (2) anemia for age, (3) elevation of alanine aminotransferase, (4) platelets after 7 days ≥450,000/mm3, (5) white blood cell count ≥15,000/mm3, and (6) urine ≥10 white blood cells/HPF.6
KD indicates Kawasaki disease; NA, not applicable.

KD is the leading cause of acquired heart disease in children in developed countries; its most serious complication is coronary artery lesions (CALs), including coronary artery fistula formation, coronary artery dilatation, and coronary artery aneurysm. Without treatment, ∼20% to 25% of children with KD develop CALs, which can cause myocardial infarction and death.4,6 In our review of the literature, there were no reports or expert recommendations regarding KD in patients with SCD. We report 2 children with SCD who presented with fever and were ultimately diagnosed with KD.

RESULTS

Patient 1

A 3-year-old girl with Hb SC disease presented for a routine hematology visit with upper respiratory symptoms and low grade fevers (maximum temperature of 37.8°C) for 1 week. She had a diffuse papular rash, consistent with viral exanthem. Complete blood count with differential and reticulocyte count were at baseline.

Two days later, the patient returned to clinic with daily fever >38.3°C, persistent rash that was now pruritic, and periorbital edema. Her tongue was erythematous with overlying white plaque, and she had developed white vaginal discharge. Hb and reticulocyte count were again at baseline. Blood and urine cultures were negative. She was managed as an outpatient with ceftriaxone for fever, nystatin for presumed oral thrush, and clotrimazole for presumed vaginal candidiasis.

The patient presented to clinic again 5 days later with continued fevers and new abdominal pain. Her fingers, toes, and inguinal creases had begun to desquamate. She had a negative nasopharyngeal viral nucleic acid swab and a negative urinalysis and urine culture, and was discharged home.

Five days later, she presented to the emergency department for persistent fevers >38.3°C. She had new bilateral conjunctival injection and cough, but had no sore throat, lymphadenopathy, rhinorrhea, or congestion. Viral testing, including for Epstein-Barr virus (EBV), cytomegalovirus (CMV), and parvovirus, was negative. Oral clindamycin was prescribed as empiric treatment for presumed streptococcal infection causing scarlet fever.

The child again presented to clinic 2 days later with continued fevers and abdominal pain. Her hands and feet continued to desquamate and her conjunctivae remained injected. Due to daily fevers of >38.3°C for 15 days without a source, she was admitted to the hospital for further evaluation. During admission, she had fevers daily up to 39.5°C. Echocardiogram obtained out of concern for KD was normal without cardiac dysfunction, coronary artery dilatation, or aneurysms. Microbiology studies, including EBV, CMV, bartonella, Mycoplasma pneumoniae, adenovirus, human herpes virus-6, respiratory viral nucleic acid panel, and blood cultures were all negative. Laboratory studies are shown in Table 1.

While this child only met 3 major criteria for KD, her laboratory studies fit the supplemental criteria for diagnosis of atypical KD. An ophthalmological examination diagnosed anterior uveitis, often seen in the acute phase of KD.5 She was treated with intravenous immunoglobulin (IVIG) 2000 mg/kg×1 dose and high dose aspirin (100 mg/kg/d) every 6 hours for 2 days. She had no further fevers after IVIG infusion and was discharged home after a 4-day admission on low-dose aspirin (4 mg/kg/d) daily for 4 weeks. All symptoms resolved by the time of outpatient follow-up 2 weeks later. Follow-up echocardiogram at that time demonstrated normal coronary artery dimensions without aneurysm and she had no further symptoms.

Patient 2

A 3-year-old boy with Hb SC disease presented with fevers, rhinorrhea, and right knee pain. He had red, injected conjunctivae, but no lymphadenopathy or erythema of the oropharynx. Hb and reticulocyte count were at baseline. He was admitted to the hospital for observation and empiric antibiotics due to sepsis risk. His knee pain was treated with ibuprofen and he received trimethoprim/polymyxin B ophthalmic ointment for conjunctivitis. He had fevers ranging from 36.7 to 40.6°C during this admission; he had no fever documented on day 3 of his hospitalization, but his fever returned the following day and he remained febrile until the morning of discharge. Nasopharyngeal swab detected rhinovirus/enterovirus. Blood cultures were negative.

During hospitalization, he developed neck pain with decreased range of motion. Neck ultrasound demonstrated bilaterally enlarged lymph nodes, up to 1.4 cm in greatest diameter on the right side and 1.9 cm on the left side. He did not exhibit meningismus. Due to his fever and tender, enlarged lymph nodes, he was treated with clindamycin for presumed bacterial lymphadenitis. His neck pain improved within 24 hours of clindamycin initiation and he was discharged home.

At follow-up 20 days after initial admission, his fevers had resolved but neck pain continued. He had persistent conjunctival injection, desquamation and erythema to his bilateral palms, and prominent tongue papillae. He had tender cervical lymphadenopathy with refusal to turn his head laterally but no meningismus. By ultrasound, his anterior cervical chain lymph nodes measured up to 3.2 cm and laboratory tests supported an inflammatory process (Table 1). EBV, CMV, and bartonella testing were negative. Electrocardiogram was normal, but echocardiogram revealed mild diffuse dilation of the left main (0.32 cm, zsc 2), left anterior descending (0.27 cm, zsc 2.9), and right main coronary arteries (0.29 cm, zsc 2.9), plus an area of dilatation (∼3×3 mm) at the bifurcation of the circumflex and left anterior descending coronary arteries. In contrast, an echocardiogram performed during a prior febrile illness showed a dilated proximal right coronary artery (0.29 cm, zsc 3.1), but the other coronary arteries were normal.

With his 10-day fever duration and symptoms, he met criteria for a KD diagnosis. He was treated with IVIG 2000 mg/kg×1 dose and low-dose aspirin (4 mg/kg/d) daily. One week after discharge, his symptoms had completely resolved. He had persistent mild right coronary ectasia on his echocardiogram 5 months postdiagnosis and continued aspirin; echocardiogram 1 year later showed resolution of ectasia and aspirin was discontinued.

DISCUSSION

Due to their functional asplenia, children with SCD are at an increased risk for invasive bacterial infection. Prompt medical evaluation of fever is essential in preventing sepsis and death. Given the heightened risk and potential complications, guidelines direct medical providers to treat febrile patients for presumed bacterial infection.3

In the era of penicillin prophylaxis and pneumococcal immunizations, sepsis occurs much less commonly in children with SCD. It remains necessary to remember that fever in children with SCD may be the presenting symptom for other SCD complications, such as acute chest syndrome and parvovirus aplastic crisis. Fevers may be the manifestation of a process entirely separate from SCD, as in the 2 cases presented above. These children received appropriate initial empiric treatment for fevers in SCD, but alternate sources were not pursued until symptoms persisted for an extended period.

KD can lead to serious complications, including CALs and heart failure. Coronary artery dilation (CAD) is a common finding in individuals with SCD due to their chronic anemia and elevated cardiac output. In a cohort of 101 children with SCD, 58% had dilation of at least 1 coronary artery while asymptomatic.7 Since CAD is frequent in those with SCD, the diagnosis of KD CALs may be more difficult to establish in this population. The coronary artery findings at the time of KD diagnosis in our second child were more significant than during a prior febrile illness, suggesting that they were reflective of KD and not merely related to increased cardiac output due to fever. KD must be considered early in the course of an unexplained febrile illness, as timely intervention is necessary in preventing severe sequelae.6

The overall estimated annual incidence of KD in children younger than 5 years of age in the United States is 20 per 100,000. In a retrospective analysis of KD hospitalizations, African Americans had the second highest incidence (after Asian and Pacific Islanders) at 17.5 per 100,000 children.8 Given this statistic, KD should be a considered as a differential diagnosis in similar clinical scenarios. Appropriate interdisciplinary services should be involved; the rheumatology, infectious disease, and ophthalmology services were consulted in the case of the first child and infectious disease and cardiology were consulted in the case of the second child. At our institution, KD is managed primarily by the infectious disease service; cardiology is consulted if echocardiograms are abnormal, and rheumatology is consulted if patients do not respond to initial treatment. Institutions may benefit from implementing a multidisciplinary team or protocol for diagnosis and treating KD as a complex multisystem inflammatory syndrome.

It should be noted that in the era of the coronavirus disease 2019 pandemic, a condition called multisystem inflammatory syndrome in children (MIS-C) has been described. Patients with MIS-C often present 2 to 4 weeks after acute coronavirus disease 2019 infection with symptoms similar to KD, including fever, conjunctivitis, peripheral edema, diarrhea, and increased markers of inflammation and cardiomyopathy. Among other serious complications attributed to MIS-C, 18.6% of affected children developed CAD or aneurysm.9 As previously described, children with SCD are already at risk for CAD. Thus, while it is essential to treat patients with SCD with fever for potential bacterial infection, it is also crucial for health care providers to consider alternative sources that could lead to other adverse outcomes.

REFERENCES

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Keywords:

sickle cell disease; Kawasaki disease; pediatric

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