Introduction

Human ehrlichiosis is an acute febrile tick-borne disease considered a zoonotic infection, caused by bacteria of the Ehrlichia genus, being Ehrlichia chaffeensis the most common cause¹-⁴. Most cases are reported in adults from the eastern and southcentral regions of the United States of America (USA), and 49% require hospitalization⁵,⁶. Death occurs in 1-2% of untreated infections, and symptoms may be indistinguishable from other conditions, such as other vector-borne diseases, meningoencephalitis, or the recently described multisystem inflammatory syndrome in children (MIS-C); thus, diagnostic suspicion is needed to initiate antimicrobial therapy, especially when tick bite history is lacking⁷-⁹.

Only twenty-three cases of human ehrlichiosis in children and adolescents outside of the USA have been reported to date⁴,⁷,¹⁰-¹⁵. We present the first pediatric case of ehrlichiosis in Mexico and the fourth in Latin America. We also performed a literature review of Ehrlichia spp infection affecting children to identify demographics, clinical characteristics, and outcomes.

Clinical case

We present the case of a previously healthy 15-year-old female from an urban area in northeastern Mexico presented to the emergency department with a five-day history of persistent fever, chills, malaise, headache, myalgias, arthralgias, vomiting, and generalized rash. Four days earlier, her neighbor had been admitted to our hospital with septic shock and disseminated intravascular coagulation (DIC) and died within 8 hours of admission with no infectious agent identified. On directed questioning, the parents admitted having three tick-infested dogs that had died the previous week. Upon admission, vital signs evidenced a fever of 38.8°C, tachycardia, tachypnea, and hypotension. In addition to an altered level of consciousness, her physical examination revealed meningeal signs, along with a maculopapular rash that involved palms and soles, and a skin lesion of 1 cm in diameter, with a necrotic central area and surrounding erythema in her left ankle (Figure 1). A clinical syndrome of meningoencephalitis was diagnosed. In addition, the possibility of a tick-borne infection was raised by considering the history of tick-infested dogs and the epidemiological link to the deceased neighbor.

Figure 1 Maculopapular rash in a patient with ehrlichiosis. Black arrow: 1 cm erythematous macule with a necrotic central area corresponding with tick-bite. 

Laboratory results demonstrated anemia and thrombocytopenia in the complete blood count: hemoglobin 9.6 g/dL (normal range: 12-14 g/dL); white blood cells 6,200/mm³ (normal range: 4,000-11,000/mm³); neutrophils 4,650/mm³ (normal range: 2,000-7,500/mm³) (75%); lymphocytes 1,240/mm³ (normal range: 1,000-4,800/mm³) (20%); platelets 116,000/mm³ (normal range: 150,000-450,000/mm³). Also, mildly elevated serum hepatic transaminase values were detected: alanine aminotransferase 71 UI/L (normal range: 4-36 UI/L); aspartate aminotransferase 77 UI/L (normal range: 8-33 UI/L); elevated acute phase reactants: C-reactive protein 90 mg/L (normal range: <10 mg/L); erythrocyte sedimentation rate 25 mm/h (normal range: 0-20 mm/h); hyperfibrinogenemia 650 mg/dL (normal range: 200-400 mg/dL), and elevated lactic dehydrogenase 366 UI/L (normal range: 140-280 UI/L); D-dimer 859 ng/ml (normal range: <500 ng/ml) and serum ferritin 223 ng/ml (normal range: 12-150 ng/ml). Nasopharyngeal swabbing for PCR (polymerase chain reaction) detection of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), serum IgM, and IgG serology were negative. Head computed tomography was normal, with no meningeal enhancement reported by the Neuroradiology Department. A lumbar puncture was performed, demonstrating a high opening pressure of 320 mmH₂O (normal range: 70-180 mmH₂O) with a clear cerebrospinal fluid (CSF) appearance. CSF white blood cell count 402/mm³ (normal range: < 5 cell/mm³); 90% polymorphonuclears; pH: 8.5; glucose 59 mg/dL (normal range: 45-80 mg/dL); proteins 107 mg/dL (normal range: 15-45 mg/dL); chloride 122 mmol/L (normal range: 120-130 mmol/L); some crenated erythrocytes; lactate 2.4 mmol/L (normal range: 1.5-1.9 mmol/L), and no microorganisms were observed on Gram stain. CSF and blood cultures were also sent. Electroencephalogram (EEG) showed bilateral and diffuse cortical and subcortical moderate dysfunction with no epileptic activity. CSF PCR FilmArray Meningitis/Encephalitis Panel (BioFire^®) and serologic titer tests for tick-borne diseases were requested, but they were not processed due to in-house laboratory unavailability of reagents. A serum sample for detecting some tick-borne diseases by PCR was sent to the Center for Research and Development in Health Sciences (CIDICS) of the Universidad Autónoma de Nuevo Léon. This test included molecular detection of Rickettsia spp, Babesia spp, Anaplasma spp, and Ehrlichia spp. Empirical therapy for meningoencephalitis was initiated with intravenous ceftriaxone (100 mg/kg/day) and vancomycin (60 mg/kg/day). Taking into consideration a high suspicion of tick-borne infections, doxycycline (100 mg/twice a day via nasogastric tube) was also included. The patient was admitted to the pediatric intensive care unit, requiring invasive mechanical ventilation and vasopressors for three days. Ceftriaxone and vancomycin were suspended after 72 hours, as CSF and blood cultures did not report any bacterial growth. Doxycycline was continued for seven days as rickettsial disease persisted as the main diagnostic impression. The patient showed subsequent clinical improvement, which allowed her transfer to the General Pediatrics ward on her seventh day of hospital stay. A week after admission, the serum PCR detection of Ehrlichia spp. was reported. No adverse or unanticipated events related to treatment or hospitalization occurred, and the patient was discharged after ten days of hospital stay with complete resolution of symptoms.

Discussion

Tick-borne diseases (TBD) are caused by bacteria, viruses, and parasites, including Anaplasma phagocytophilum, Babesia spp., Borrelia burgdorferi, Ehrlichia spp., Powassan virus, Rickettsia spp., among others¹⁶,¹⁷.

Ehrlichiosis is caused by bacteria from Ehrlichia genus, including E. chaffeensis, E. ewingii and E. muris subsp. Eauclairensis¹-⁴. Ehrlichia spp. are Gram-negative, obligate intracellular bacteria that grow in leukocytes in membrane-bound vacuoles and can infect humans and other vertebrate mammals, such as deer, rodents, dogs, sheep, and goats, and thus considered a zoonotic infection. Furthermore, its clinical presentation has been primarily described in adults¹-⁴.

E. chaffeensis is the most common cause of human ehrlichiosis. Dawson et al. reported the first case in 1991¹-⁴,¹⁸. The frequency of ehrlichiosis is rising, probably due to increased clinical recognition and availability of serological and molecular diagnostic tests¹⁹.

Ehrlichiosis is primarily acquired through the bite of an infected tick, although cases of spread through blood transfusion and organ transplant recipients have been reported³,⁴,²⁰. It has been demonstrated that E. chaffeensis can survive for up to a week in refrigerated blood³.

Ticks that can spread the bacteria to humans include Ixodes scapularis (black-legged tick), found in southcentral and eastern USA, transmitting E. muris subsp. eauclairensis, and Amblyomma americanum (lone star tick), which spreads E. chaffeensis and E. ewingii, and is distributed in eastern USA³,²⁰,²¹.

Ticks become infected after feeding from their primary reservoir host, such as the white-tailed deer (Odocoileus virginianus) for the lone star tick²⁰,²². Transmission to humans usually occurs during summer months, with a reported peak during June and July, and is most frequently reported in men than women³,⁴,²³,²⁴.

We performed a literature search of core databases including Medline (US National Library of Medicine [NLM]), SciELO (Scientific Electronic Library Online), LILACS (Latin American and Caribbean Literature in Health Science), Scopus (Elsevier, Amsterdam, Netherland), the Excerpta Medica Database (Embase [Elsevier, Amsterdam, Netherlands]) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL [EBSCO, Ipswich, Massachussetts]) Other databases included Europe PMC (European Bioinformatics Institute) and Web of Science (Clarivate Analytics, Philadelphia, Pennsylvania) between 1989 and 2021 using a combination of the keywords "Ehrlichia spp", "Ehrlichiosis", "human monocytic ehrlichiosis" with a narrow search specific to pediatric cases (0-18 years). We included articles published between January 1989 and May 2021, with children and adolescents between 0 and 18 years of age and a confirmed Ehrlichia spp. infection. All case reports and case series were included, and references were reviewed to identify additional cases and to detect duplicates.

We identified twenty-three cases of ehrlichiosis in children and adolescents, including the present case⁴,⁵,⁷,¹⁰,¹²-¹⁴,²⁰,²⁵-³⁴. A summary of the cases of pediatric ehrlichiosis is shown in Table 1.

Similar to what has been previously described in adults, we found a slightly higher predominance of ehrlichiosis in males (male-to-female ratio 1.1:1), and E. chaffeensis was the most frequently identified species, corresponding to 47.8% (n = 11)³,²³,³⁵.

Signs and symptoms of ehrlichiosis generally appear within one or two weeks after the bite of an infected tick. It is important to mention that tick bites are typically painless, thus some patients may not notice them³,⁴,²⁰-²². We found that tick exposure or tick bite was only reported in 65.2% (n = 15) of children and adolescents. In this patient, exposure was demonstrated, as the family acknowledged having tick-infested dogs that had recently died. Although the parents did not explicitly refer history of a tick bite, the physical examination demonstrated a skin lesion compatible with a tick bite.

Infection with Ehrlichia spp. ranges from asymptomatic to fatal illness³,⁴,²¹. It has been reported that up to 13% of children in endemic areas may present an asymptomatic infection²¹. In those who present symptoms, early manifestations of the disease include fever, chills, fatigue, headache, myalgia, arthralgia, nausea, vomiting, loss of appetite, diarrhea, cough, and petechial or maculopapular rash involving the trunk, which presents in children in up to 66% of the cases, compared to 36% to 47% of infected adults³,⁴,¹⁵,²⁰-²²,³⁰,³⁶. Although clinical manifestations of ehrlichiosis may be similar in adults and children, some tend to appear more frequently in younger patients, such as neurological involvement and rash³,¹⁵,³⁷.

A retrospective study including 32 children with confirmed or suspected ehrlichiosis in six areas located in the "tick belt" of the Southeastern United States, of which only 14 were confirmed cases, found the following prevalence of symptoms: fever 100%, headache 69%, myalgia 69%, rash 66%, nausea or vomiting 56%, altered mental status 50% and lymphadenopathy 47%³⁵.

The triad of fever, headache, and petechial or maculopapular rash, associated with rickettsial diseases, was only present in 48% of our cases²⁹,³⁸. Although not presented all concomitantly, those three symptoms were the most common. This clinical triad was present in our patient.

Fever was reported in all cases. Rash and headache were present in 60.9% (n = 14) and 52.1% (n = 12), respectively. Altered mental status was present in 52.1% (n = 12) and abdominal pain in 39.1% (n = 9) of cases (Table 2).

Data on symptom duration was available in 19 out of 23 cases, ranging from 1 to 30 days. The median duration of symptoms prior to antimicrobial therapy and hospitalization was seven days, similar to the six to nine days of medians previously reported¹⁹,³⁵.

If antibiotic treatment is delayed, late manifestations of the disease can cause severe illness with various complications, including septic shock, meningoencephalitis, respiratory failure, DIC, organ failure, and death³,⁴. Another complication that has been related to ehrlichiosis is hemophagocytic lymphohistiocytosis (HLH)²⁰,²². Some risk factors described for severe illness include antibiotic treatment delay, young or old age, and immunocompromise, such as leukemia, solid organ transplants, and human immune deficiency virus³,²⁰,²¹,²⁴.

Of 23 cases, only one had risk factors for severe disease, with a history of immunosuppressive therapy with prednisone and azathioprine secondary to a solid organ transplant; however, this patient had a favorable outcome and did not develop life-threatening complications²⁹.

Severe ehrlichiosis, defined as an illness with complications, was present in 82.6% (n = 19). Complications were reported as follows: DIC (n = 10, 43.4%), HLH (n = 7, 30.4%), meningoencephalitis (n = 9, 39.1%), hypotension (n = 7, 30.4%), respiratory failure (n = 4, 17.3%), septic shock (n = 3, 13%), and need of extracorporeal membrane oxygenation (n = 2, 8.59%).

Laboratory findings in ehrlichiosis include leukopenia, thrombocytopenia, anemia, and elevated transaminases. These last three laboratory alterations were observed in this case report. Other less common findings include hyponatremia and hypoalbuminemia²¹. According to Schutze et al. in their review of confirmed and suspected cases of ehrlichiosis, the most common were thrombocytopenia (94%), elevated aspartate aminotransferase (90%), elevated alanine aminotransferase (74%), hypoalbuminemia (65%), lymphopenia (57%), leukopenia (56%) and hyponatremia (55%)³⁵. Common findings in our review were thrombocytopenia (95.6%), elevated aspartate aminotransferase and elevated alanine aminotransferase (65.2%), lymphopenia (26%), leukopenia (69.5%). We found incomplete data on laboratory values concerning sodium and albumin. Hyponatremia and hypoalbuminemia were reported in 13% and 8.6% of the cases, respectively. Although elevated band count is not reported in the literature as part of the laboratory findings, it was remarkable that six patients (26%) had high counts of immature neutrophils²⁵-²⁸,³⁰.

Diagnosis of ehrlichiosis remains challenging, partly because the clinical presentation may not be easily differentiated from other febrile diseases of higher prevalence in certain areas. Also, because serological and molecular confirmatory tests may be expensive and not extensively available. Differential diagnoses include influenza-like illnesses, other vector-borne diseases (dengue fever, rickettsiosis, babesiosis, malaria), meningoencephalitis, including meningococcal infection, and the recently described multisystemic inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 virus infection⁸,³⁸,³⁹. Given the non-specific clinical presentation, a proper assessment is necessary, including laboratory tests to support the clinician in the diagnosis, considering the possible etiologies based on the epidemiological context and the patient's personal history.

Among confirmatory tests, we found DNA via PCR, isolation of E. chaffeensis from a clinical specimen in cell culture, Ehrlichia antigen in a biopsy, and an increase in titers of 4-fold or higher between acute and convalescent serum using indirect immunofluorescence antibody assay specific for IgG against Ehrlichia antigen²⁴,⁴⁰.

Although not readily available at many centers, other methods to confirm ehrlichiosis include the detection of DNA by PCR on a clinical specimen, detection of Ehrlichia antigen by immunohistochemical methods in a biopsy or autopsy, or isolation in a cell culture from a clinical specimen. PCR on whole blood during acute illness is an effective and efficient method to confirm ehrlichiosis, as it provides evidence of infection with Ehrlichia spp, and can differentiate between species²⁴. These molecular techniques were implemented in dogs and humans in the 90s; previously, the diagnosis was mostly made by serological methods⁴¹. In this literature review, we included cases dating back to 1989. From 1999 to date, we found 13 patients diagnosed by PCR detection (n =13, 56.50%).

The availability of molecular tests to detect Ehrlichia spp was pivotal to diagnosing this case as a tick-borne infection, even though the results were not available rapidly. Another limitation to assess this case was the unavailability of diagnostic tests such as the PCR FilmArray Meningitis/Encephalitis Panel (BioFire^®) since it includes 14 of the most frequent pathogens that cause meningoencephalitis. Also, the lack of a confirmatory serological test for ehrlichiosis that could evidence specific antibody increase from acute and convalescent serum.

Doxycycline is the treatment of choice for adults and children and should be continued at least 3 days after the last documented febrile episode²⁴,³⁷. The recommended dosage in children is 4 mg/kg per day, every 12 hours⁴. It is well tolerated by children as a 10-day course, and there is no evidence of tooth discoloration with such regimes²¹,²⁴. Considering that antimicrobial delay is associated with severe disease and adverse outcomes, antibiotic therapy should be initiated immediately if the diagnosis is suspected, regardless of pending laboratory work-up or results³,⁴,²¹,²⁴,³⁷. In this case, the initial clinical presentation, the epidemiological link, and the history of tick exposure were important to suspect a TBD and initiate empirical therapy. Early initiation of doxycycline was pivotal for the survival of our patient.

If appropriate antimicrobial coverage has been established but the fever persists for 48 to 72 hours, another diagnosis or complication, such as HLH, should be considered⁴,⁵,¹⁰,²⁰,³¹,³²,³⁴. In the reviewed cases, persistent fever despite antimicrobial therapy was reported in patients with HLH (30.8%, n = 7).

The reported fatality rate is 1% to 3%, being the highest among the elderly, children, and immunocompromised⁴,²⁰,²². In our review, death occurred in two previously healthy children, corresponding to 8.6% of the cases.

The greatest preventive measure for ehrlichiosis is avoiding exposure to tick bites. The recommendation is to perform tick checks regularly in humans and pets, particularly after returning from tick-infested areas. Another measure is wearing full-coverage clothing, preferably treated with permethrin and repellents containing n,n-diethyl-m-toluamide (DEET)¹⁷,²⁴.

Although the presence of antibodies against TBD has already been reported in personnel working in veterinary clinics⁴², in Mexico, only four cases of human ehrlichiosis in adults have been reported¹,²,⁴³,⁴⁴. The first case was reported in 1996 in a 41-year-old male from southern Mexico². In 2013, two female cases were reported, one of them with a fatal outcome (a 31-year-old female from central Mexico)¹,⁴³. Recently, in 2020, another male case from Mexico City was documented⁴⁴. No additional reports of ehrlichiosis in Mexico involving children were found, and neither cases occurring in the country's northern region. This is the first case of pediatric ehrlichiosis in Mexico and the first case in the north of Mexico.

Ehrlichia spp is not a frequent pathogen related to disease in children, partly because of the lack of widespread availability of diagnostic tools. Infection with these bacteria should be considered in those patients with a fever with known or possible exposure to ticks, especially in endemic areas, since the prevalence in dogs has been estimated at up to 44%⁴⁵. Given that the clinical presentation could be indistinguishable from other diseases caused by arboviruses, other TBDs, meningoencephalitis, and MIS-C, ehrlichiosis should also be considered as a differential diagnosis in patients with a fever, rash, and altered mental status, even with no history of a tick bite. If the diagnosis of ehrlichiosis is suspected, antimicrobial therapy with doxycycline should be initiated readily to avoid progression to severe illness and life-threatening complications.