Severe Fatal ARDS Due to Untreated Human Granulocytic Anaplasmosis in a 67-Year-Old Man: A Case Report

Introduction

Tick-borne diseases (TBDs) have emerged as a significant public health concern in the United States (US) due to their increasing incidence and geographical spread [1]. Human granulocytic anaplasmosis (HGA) is a tick-borne illness caused by the obligate intracellular bacterium Anaplasma phagocytophilum [2–4]. It is primarily transmitted through the bite of infected black-legged ticks, including Ixodes scapularis (deer tick) and Ixodes pacificus (western black-legged tick) in the endemic regions in the US [2–4]. Anaplasmosis was first described in the US as a human disease in the mid-1990s and became notifiable in 1999 [5]. Since then, the number of cases reported to the Centers for Disease Control and Prevention (CDC) has steadily increased from 348 cases in 2000 to 6729 cases in 2021, primarily among males and those above 40 years of age [5]. It has a low case fatality rate of less than 1% and patients with immunocompromised states may be at risk of severe infection [5].

The clinical manifestations of HGA vary from asymptomatic infection to mild nonspecific febrile illness (fever, myalgia, arthralgia, headache, diarrhea) to severe multi-system involvement [2,6]. Respiratory system involvement, including pneumonia, acute respiratory distress syndrome (ARDS), and pleural effusion, are uncommon [2,6]. Diagnosis of HGA can be confirmed using serology testing, detection of morulae inside the neutrophils, DNA detection by PCR, or isolation by culture [4]. A 14-day to 21-day course of doxycycline is the first-line treatment for HGA [4]. This report describes a 67-year-old male resident of rural Pennsylvania, admitted to the hospital after a fall, who developed fatal acute respiratory distress syndrome (ARDS) associated with human granulocytic anaplasmosis (HGA) following transmission of Anaplasma phagocytophilum by a tick bite (Ixodes scapularis).

Case Report

A 67-year-old man, a resident of rural Pennsylvania, with past medical history of diabetes mellitus, presented in May of 2023 with a fall from a 7-foot-tall ladder, sustaining right-sided hemopneumothorax, multiple right rib fractures, and unstable T12 vertebra fracture. A right chest tube was placed as an emergency measure. Admission labs showed anemia (Hb 7.3 gm/dl), leukopenia (WBC 3.6 K/L), thrombocytopenia (115 K/L), mild transaminitis (AST 60 U/L, ALT 79 U/L). He also underwent T9-L2 posterior spinal fusion surgery on hospital day 2. Postoperatively, he required up to 4 L/min nasal cannula oxygen on day 1 and was getting aggressive pulmonary hygiene, incentive spirometry, and right vertebral nerve block for pain control. His course deteriorated on postoperative day 2 when he was transitioned to high-flow nasal cannula oxygen due to worsening hypoxemia. A chest X-ray (CXR) did not show any worsening of hemopneumothorax. A chest tube was in place, but bilateral interstitial infiltrates started showing. His respiratory status continued to worsen, and he had pulseless electrical activity (PEA) cardiac arrest due to acute hypoxemic respiratory failure. He was emergently intubated during the cardiopulmonary arrest (CPR) and return of spontaneous circulation (ROSC) was achieved after 1 round of epinephrine and chest compressions. Due to the concern for aspiration pneumonia, patient was started empirically on iv Unasyn, and emergent bronchoscopy was performed and a bronchoalveolar lavage (BAL) sample was sent. His oxygenation continued to worsen, and he developed worsening pulmonary infiltrates bilaterally, consistent with severe ARDS. He received high PEEP ventilation, prone positioning, neuromuscular paralysis, and inhaled epoprostanol to improve his refractory hypoxemia. The Cardiothoracic team was also consulted to discuss the need for extracorporeal membrane oxygenation (ECMO) support and were on standby. His ICU course got further complicated by septic shock, acute kidney injury, and new-onset atrial fibrillation. Due to worsening clinical status, Unasyn was broadened to iv vancomycin and cefepime, and stress-dose steroids were added for septic shock. He did show some improvement in oxygenation with prone positioning.

Although, our patient did not report any history of tick bites and had no pets, he liked to spend time outdoors. Due to worsening thrombocytopenia, leukopenia, and transaminitis, and residence in the endemic region, we had his blood tested for tick-borne infections: PCR for anaplasmosis, Ehrlichia Chaffeensis, babesiosis, rocky mountain spotted fever, and serum antibody titer for Lyme disease. BAL for bacterial, fungal, viral pathogens, COVID-19, respiratory viral panel, mycoplasma pneumoniae, chlamydia pneumoniae were negative, and urine legionella and urine streptococcal pneumoniae antigens were also negative.

Hiss family arrived from out of state on hospital day 4 and decided to withdraw medical care on hospital day 5 knowing the patient’s own wishes. He died after his care was transitioned to comfort care measures only. Blood tests for the tick-borne illnesses Babesia, Ehrlichia, and Lyme were negative, but PCR for Anaplasma DNA came back positive after the patient’s death. A peripheral smear was then examined using Wright stain, showing morulae inside the cytoplasm of infected neutrophils (Figure 1).

Discussion

We describe a case of a 67-year-old man, a resident of rural Pennsylvania, who presented after a fall and developed atypical presentation of severe fatal ARDS due to HGA, which is caused by the Anaplasma phagocytophilum bacterium. Vectors for transmission include Ixodes ricinus complex-Ixodes scapularis (deer tick), and Ixodes pacificus (western black-legged tick) in the US [7]. The endemic areas include New England, the upper Midwest, mid-Atlantic, and northern California.

Typical presentation includes nonspecific flu-like illness with fevers, headache, myalgias, arthralgias, and diarrhea, with or without history of tick bite or bite marks [6]. Classic laboratory abnormalities indicative of HGA are leukopenia (present in 50% of cases), thrombocytopenia (94%) and transaminitis (90%) [8]. HGA shows seasonal variation, with most cases reported in spring and summer months, correlating with higher tick activity [9]. There has been at least a 20% increase in tick-borne illnesses in this decade due to climate changes leading to warmer winters and increased precipitation, favoring tick survival [9].

Most cases of anaplasmosis are mild, 36% need hospitalization, and approximately 3% present with severe life-threatening complications [10]. Table 1 lists the uncommon systemic complications and associations reported with anaplasmosis, including neurologic (stroke, encephalopathy), cardiac (myopericarditis), renal (acute kidney injury, rhabdomyolysis), respiratory (pneumonia, ARDS), hemophagocytic lymphohistiocytosis (HLH), and macrophage activation syndrome [10–45].

Respiratory complications are an uncommon but serious presentation of human granulocytic anaplasmosis. So far, only 14 cases (including ours) of HGA associated with respiratory failure are reported in the literature – 10 with pneumonia and 4 with ARDS [10,19–27]. Table 2 lists the summary of reported cases of HGA with respiratory failure. The mean (SD) age of this patient cohort was 64 (11) years and included 8 females. Most of the reported cases were from the US, and all resided or traveled to endemic regions with high tick activity. Invasive mechanical ventilation was required in 6 out of 14 cases, including all 4 with ARDS. The mean duration of mechanical ventilation was 3.25 days. All mechanically ventilated patients were successfully extubated, except for 1 with bilateral pneumonia requiring tracheostomy for long-term ventilator support. The pathophysiology of ARDS due to HGA is incompletely understood, but is likely due to an exaggerated inflammatory response due to infection of neutrophils [23]. Dysregulated inflammatory reaction also could explain clinical and laboratory features of HLH, and macrophage activation syndrome is reported in patients with HGA [36–39].

Diagnosis of HGA can be challenging and requires high clinical suspicion (Table 3). Serologic conversion may take 2–4 weeks after a tick bite; therefore, indirect fluorescent antibody testing should be repeated in 2–3 weeks, and a 4-fold rise in antibody titer is diagnostic [23]. Polymerase chain reaction (PCR) is confirmatory but may not be readily available at all institutions. Early diagnosis can be made by Wright- or Giemsa-stained peripheral smear showing morulae inside neutrophils (seen in 25–75% of cases) [23].

Doxycycline (100 mg twice daily) is the drug of choice and should be started immediately based on strong clinical suspicion, without awaiting positive results [3]. Response to doxycycline is excellent and is associated with favorable outcomes. Pregnant patients and those with allergy to doxycycline can receive rifampin [3]. The outcomes of patients with HGA-associated respiratory failure are good with timely administration of appropriate antibiotics. Our patient was at high risk for complications due to advanced age and comorbidities (eg, diabetes mellitus) and did not receive doxycycline, which could have contributed to his poor clinical course and outcome.

Conclusions

This report describes a case of HGA and highlights that in parts of the world where tick-borne diseases are endemic, disease awareness and early diagnosis and management are required. HGA can have atypical presentation with respiratory failure due to pneumonitis, or ARDS, adding to the diagnostic dilemma. Doxycycline administration can be a simple and lifesaving intervention in these patients and should be considered as part of empiric antibiotic therapy for community-acquired pneumonia in such high-risk (eg, advanced age, comorbidities) patients.