Human Monocytic Ehrlichiosis A Potentially Severe Disease in Children

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Human Monocytic Ehrlichiosis: A Potentially Severe Disease in Children

The spectrum of diseases caused by human monocytic ehrlichiosis (HME) in

children ranges from asymptomatic to severe and even fatal.1-5 The infection

often goes unrecognized1, 6 because it may be very mild and not lead the

family to seek medical attention, or because the physician may not be

familiar with it. The importance of diagnosing HME in children is that

appropriate early antibiotic therapy with a tetracycline leads to rapid

defervescence and recovery.2, 6, 7 Moreover, when untreated, HME may be

fatal. We report 2 cases of severe HME in children that required intensive

care management.

Report of a Case

Case 1

A 6-year-old white girl with hypotension, fever, lethargy, and pancytopenia

was transferred to the pediatric intensive care unit at the s Hopkins

Medical Institutions (Baltimore, Md) from another hospital. She had a 10-day

history of fever (temperature to 40°C), headache, prominent hyperosmia,

photophobia, tender posterior cervical lymphadenopathy, and 2 episodes of

emesis. She was receiving prophylactic trimethoprim-sulfamethoxazole, as she

had vesicoureteric reflux.

The patient had presented to her primary care pediatrician on days 3, 5, and

7 of the illness. She did not seem very sick but had a very erythematous

nonpainful pharynx. On the first visit, the trimethoprim-sulfamethoxazole

dosage was increased to treat possible sinusitis. Two days prior to

transfer, she was treated with intravenous fluids and intramuscular

ceftriaxone sodium at the emergency department; however, her condition

worsened and she was admitted on the evening prior to transfer.

She had been camping in a state park in northeastern land 7 days before

the first symptoms of illness. No tick bites were noted. Physical

examination revealed hypotension (80/40 mm Hg), tender hepatosplenomegaly,

hand and pedal edema, and nontender cervical lymphadenopathy. A faint

erythematous rash was noted on her lower limbs before but not after

transfer. She was markedly lethargic but could be aroused, and lacked focal

neurologic findings and neck stiffness.

Her initial laboratory evaluation 2 days earlier revealed pancytopenia. The

white blood cell (WBC) count was 2.1 109/L with 0.13 band forms;

hemoglobin, 111 g/L; platelets, 61 109/L; serum sodium, 128 mmol/L; and a

normal chest x-ray film. Rapid streptococcal and monospot tests were

negative. Prior to transfer, dopamine hydrochloride was administered to

maintain blood pressure, and intravenous doxycycline hydrochloride

administration was started for presumed rickettsial infection.

On arrival in the tertiary care facility, she had an elevated aspartate

aminotransferase level (133 U/L), her lactate dehydrogenase level was 729

U/L, fibrinogen concentrations were decreased, and fibrin degradation

products and D-dimer were present, but the prothrombin time and activated

partial thromboplastin time test results were normal. Her WBC count had

increased to 4.7 109/L (0.54 segmented leukocytes, 0.40 lymphocytes, 0.05

monocytes, and 0.01 atypical lymphocytes). There was no evidence of renal

dysfunction. Chest x-ray films showed bilateral pleural effusions and left

basal atelectasis. Bone marrow aspiration was performed to investigate the

pancytopenia, and revealed myeloid predominance with decreased erythroid and

lymphocytic components, and increased macrophage phagocytic activity. A

polymerase chain reaction test performed on blood collected 48 hours after

doxycycline administration was negative for Ehrlichia chaffeensis.

After the patient's transfer, doxycycline therapy was continued and

piperacillin tazobactam was added for treating a possible bacterial

infection. The patient's health rapidly improved and the following morning,

she was afebrile (36.9°C) and more alert. The dopamine infusion was

discontinued after 12 hours and she was discharged on the fifth day

following transfer, completing a total of 10 days of doxycycline therapy.

The diagnosis of HME was confirmed by demonstrating the rising titer of E

chaffeensis antibodies in serum obtained at first presentation (titer <80)

compared with 3 days later (titer 1280). Two months after discharge, she had

fully recovered.

Case 2

A 7-year-old white girl from rural northeastern land was transferred to

a pediatric hospital intensive care unit with fever (temperature, 38.9°C),

tachypnea, hypotension, diarrhea, vomiting, and a generalized maculopapular

rash more on the extremities than the trunk. She was initially seen for

headache and malaise attributed to sinusitis, which had persisted for 1 week

and was treated with oral amoxicillin. Additional medical history revealed

that a " large tick " had been removed 2 weeks before presentation. Because of

her progressive clinical deterioration, she was given 1 dose of ceftriaxone

sodium and transferred to the pediatric intensive care unit, where empirical

piperacillin sodium, oxacillin sodium, and gentamicin sulfate were

administered for 6 more hours.

Physical examination revealed nontender hepatosplenomegaly, easy bruising,

petechiae, and occasional rhonchi on auscultation. The neck was supple and

no neurologic signs were noted. A chest roentgenogram revealed bilateral

infiltrates. Laboratory evaluation revealed a WBC count of 1.8 109/L (0.50

granulocytes, 0.39 lymphocytes, 0.02 monocytes), a hemoglobin concentration

of 113 g/L, a reticulocyte count of 0.004 (normal range, 0.005-0.015), and a

platelet count of 46 109/L. Prothrombin time was 13 seconds (normal range,

9-11.5 seconds); serum sodium, 130 mmol/L; aspartate aminotransferase, 667

U/L (normal range, 15-37 U/L); alanine aminotransferase, 291 U/L (normal

range, 30-65 U/L); lactate dehydrogenase, 1363 U/L (normal range, 191-381

U/L); and arterial blood gas on room air revealed a pH of 7.32, PCO2 of 37

mm Hg, PO2 of 64 mm Hg, and HCO2 of 19 mm Hg. Therapy with ceftazidime,

gentamicin, erythromycin, and chloramphenicol was administered for the next

30 hours.

The initial 18 hours were stormy, with profound respiratory failure

requiring mechanical ventilation and most likely representing acute

respiratory distress syndrome. Within 10 hours, the hypotension worsened and

was accompanied by ascites, peripheral edema, and bilateral chest tube

placement. The patient developed disseminated intravascular coagulation with

an activated partial thromboplastin time of 77 seconds (normal range, 23-38

seconds), a fibrinogen level of 32 µmol/L (normal range, 4.4-11.0 µmol/L),

and D-dimers greater than 1000 ng/mL (normal, <500 ng/mL). She required

pressors and transfusions of red blood cells, fresh-frozen plasma,

cryoprecipitate, and platelets. Bone marrow examination revealed hyperplasia

of myeloid elements and megakaryocytes; no intracytoplasmic inclusions were

noted. After 36 hours, therapy with doxycycline was begun and continued for

14 days for possible Rocky Mountain spotted fever (RMSF) or ehrlichiosis.

Thereafter, cardiovascular and respiratory function stabilized. Cerebral

computed tomographic and magnetic resonance imaging and magnetic resonance

angiography scans showed sinusitis and cerebral edema without midline shift.

Lumbar puncture results revealed a WBC count of 0.017 109/L in the

cerebrospinal fluid, with a differential including 0.06 neutrophils, 0.06

monocytes, and 0.88 lymphocytes; cerebrospinal fluid protein level was 0.85

g/L (normal, 0.15-0.45 g/L), and the glucose level was normal. Blood, bone

marrow, urine, respiratory, and cerebrospinal fluid cultures and stains for

microorganisms were unrevealing.

Liver synthetic function returned more rapidly than respiratory function,

and the patient was extubated after 7 days of mechanical ventilation. The

rash dissipated within 1 day of the start of doxycycline therapy. During the

first 48 hours, the WBC rose to 5.0 109/L, hemoglobin level stabilized at

between 100 and 110 g/L, and fibrinogen, D-dimer, and serum lactate

dehydrogenase levels normalized. Serum transaminase levels decreased, but

remained above the normal range. There was no evidence of renal dysfunction.

A polymerase chain reaction test for E chaffeensis DNA performed 48 hours

after doxycycline therapy began (on day 9 of the illness) was negative.

Serologic tests for RMSF were negative, but E chaffeensis serum antibody

titers on day 9 of the illness were 640 and 3 weeks later, greater than or

equal to 10,240 .

On hospital day 11, the child was transferred to a rehabilitation unit with

residual neurologic signs including ataxia; bilateral lower limb clonus;

upgoing toes; a mild symmetrical hand tremor; photophobia; headache; and

cognitive deficits consisting of impaired attention, dysfunctions in memory,

calculation, and comprehension, and a flat affect. Motor and reflex signs

resolved within 1 week, but the cognitive (memory, calculation, attention,

comprehension) and affect impairment persisted for 3 more weeks. After 3

additional weeks, an outpatient visit confirmed that her appetite had

returned to her premorbid state, and that she was doing well in school.

Comment

Human monocytic ehrlichiosis is a cause of severe and potentially fatal

illnesses in children. Hypotension with a septic shock-like picture, acute

respiratory distress syndrome, disseminated intravascular coagulation,

meningoencephalitis, and opportunistic infections are features of severe HME

even in children.1-5 The lack of a recognized tick bite, as in the first

case, occurs in about 25% of pediatric HME cases.2 The gradual onset of an

apparently nonspecific febrile illness with lethargy, myalgias, headache,

nausea, emesis, cervical lymphadenopathy, pharyngitis,1, 2 or hyperosmia in

a child can make HME difficult to distinguish from viral illnesses.2, 3 It

is interesting to note that both patients described here were initially

thought to have sinusitis with headache and fever, and systemic involvement

during the first 7 to 10 days of the illness was not recognized.

Physical findings uniformly include fever in children1, 2, 4; other features

are variably present and include hepatosplenomegaly, systolic heart murmur,

and rash.1, 2 Rash is observed more frequently in children (66% of cases)

than adults,2, 3 is often macular, infrequently petechial, and may not be

prominent.2 Cervical lymphadenopathy, pharyngeal erythema, tonsillar

exudate, conjunctivitis, strawberry tongue, oral or genital ulcers,

neurologic findings (bilateral foot drop, speech and reading problems), and

hand and pedal edema are also diagnosed in children with HME.1, 2, 4, 8

Frequent laboratory findings in children with HME are pancytopenia,

particularly lymphopenia and thrombocytopenia,2 hyponatremia, elevated

aspartate aminotransferase, and abnormal coagulation test results, all of

which were present in our patients. In cerebrospinal fluid analyses,

lymphocytic pleocytosis is predominant and elevation of protein levels is

less frequent than in adults.1, 5, 8, 9 Diagnosis is best achieved by

serologic testing in convalescence. A polymerase chain reaction test for E

chaffeensis nucleic acids in blood is generally considered both sensitive

(85%) and specific (100%); however, recent results in clinical laboratory

settings have not been as encouraging,10 and indicate that samples should be

obtained prior to anti-Ehrlicia therapy.3, 6, 10

Human monocytic ehrlichiosis may occur more frequently than RMSF in endemic

areas, including land,3 where these patients were exposed. Only 10% of

HME cases reported to the Centers for Disease Control (Atlanta, Ga) occurred

in children.2 However, a seroprevalence study in northern California found

more frequent evidence of infection in children,11 suggesting that

subclinical infections with E chaffeensis occur.

The importance of considering HME as a possibility in any child who has been

in an endemic area lies in the need for early antibiotic therapy to prevent

progression to severe disease.2, 3, 6, 7, 12-14 Empiric therapy with a

tetracycline is recommended for children with suspected HME or RMSF, as this

has been associated with rapid defervescence and hematologic recovery.2, 3,

6, 7 Since E chaffeensis is resistant in vitro to chloramphenicol and the

risk of tooth staining with a single course of doxycycline is thought to be

low relative to the risk of ineffective treatment of HME or RMSF,2, 3, 6, 7

a tetracycline is the preferred drug in treating young as well as older

children.2, 3, 6, 7 Human monocytic ehrlichiosis should be considered in the

differential diagnosis of a child presenting with a febrile illness who has

been in an endemic area in the preceding 3 weeks, particularly in the

context of leukopenia, thrombocytopenia, and elevated serum transaminase

levels.1, 2 To prevent progression to severe disease, empiric antibiotic

therapy with doxycycline should be initiated in children suspected to have

HME.2, 3, 6, 7

J. Dumler, MD

The s Hopkins Medical Institutions, Meyer B1-193

600 N Wolfe St

Baltimore, MD 21287

Cybele Dey, MB, BS

Baltimore

Frederick Meier, MD

L. , MD

Wilmington, Del

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