A Case Report and Literature Review of Babesiosis-Induced Acute Respiratory Distress Syndrome

Babesiosis, a tick-borne protozoan disease, has been increasing in frequency in recent years. Familiarity with presentations of babesiosis is important for clinicians. Acute respiratory distress syndrome (ARDS) is a rarely seen complication of severe babesiosis. In most cases, the patients with babesiosis developed ARDS several days after initiation of antibabesia therapy. We present a unique case of babesiosis without any respiratory symptoms on presentation who developed ARDS within 24 hours of babesiosis treatment initiation. Furthermore, we reviewed published cases of ARDS in babesiosis.


Introduction
Babesiosis, caused by intraerythrocytic protozoan parasites of the genus Babesia, is an infectious disease that is primarily transmitted by ticks, but it can also be transmitted by blood transfusion, organ transplantation, and perinatally [1,2].
On day 1, the infectious diseases consult team recommended treatment for possible coinfection with babesiosis, Lyme disease and anaplasmosis pending full diagnostic testing. Te patient received azithromycin 500 mg IV, then doxycycline 100 mg orally (1 hour after azithromycin), and atovaquone 750 mg orally (2.5 hours after azithromycin). Te patient then became hypoxic, requiring supplemental oxygen with a fow rate of 3 liters per minute (LPM) via nasal cannula (NC) within 2 hours after the frst dose of azithromycin. Within 9 hours of initiation of antibiotics, the patient was noted to have shaking chills and cold extremities with moderate respiratory distress, without lower extremity edema, jugular venous distention, or S3 heart sound. His temperature was 38.5°C, BP 132/108 mmHg, HR 116 beats per minute, RR 26 breaths per minute, and oxygen saturation 86% on supplemental oxygen 3 LPM via NC. Chest Xray (CXR) showed mild bilateral opacities. Te patient required supplemental oxygen therapy with a fow rate of up to 10 LPM via NC, followed by high-fow NC oxygen therapy, then noninvasive ventilation with bilevel-positive airway pressure.
On day 2, the patient was intubated within 20.5 hours of antibiotic initiation for his worsening respiratory status and was transferred to the medical intensive care unit. Arterial blood gas 18 hours after intubation was pH 7.41, PaCO 2 32 mmHg, PaO 2 275 mmHg, on FiO 2 100%, positive endexpiratory pressure (PEEP) 10 cmH 2 O. A repeat CXR showed worsening bilateral opacities (Figure 2 Te patient had a recurrent fever for 5 days (days 0 to 4) with his highest daily temperatures ranging from 39.2°C to 39.5°C, then defervesced on day 5. Te patient was successfully extubated on day 6. CXR on day 7 showed signifcant improvement in bilateral opacities (Figure 2(b)). Daily smear exam showed resolution of parasitemia on day 8. Supplemental oxygen and vasopressor support (norepinephrine 2-4 mcg per minute) to maintain mean arterial pressure >65 mmHg (days 4-8) were discontinued on day 9. Te patient received a total of 10 days of azithromycin, atovaquone, and doxycycline then was discharged home on day 11.
To rule out coinfection, tests for anaplasmosis and Lyme disease were conducted on day 1, the polymerase chain reaction to detect Anaplasma phagocytophilum from the blood sample was negative. Initial two-tiered serologic testing for IgM response to Borrelia burgdorferi was positive: Lyme disease Enzyme immunoassay (EIA) index value of 2.99 (index value <0.90 is negative), positive IgM immunoblot with the presence of 23, 39, and 41 kDa protein bands (positive is reactive to ≥2 out of 3 bands), and negative IgG immunoblot with the presence of 41 and 58 kDa protein bands (positive is reactive to ≥5 out of 10 bands). On day 84, repeat two-tiered serologic testing for Lyme disease as an outpatient was negative: Lyme disease EIA index value of 1.08, negative IgM immunoblot with an absence of protein bands, and negative IgG immunoblot with the only presence of 58 kDa protein band. Case Reports in Infectious Diseases 3

Discussion
Over the past 50 years, the incidence of human babesiosis has signifcantly increased worldwide, especially in the United States (US), where most cases have been reported [1,4,14]. Since national surveillance for babesiosis began in 2011, annual reported cases doubled between 2011 (total 1,126) and 2019 (total 2,418) in the US [2] (https://www.cdc. gov/parasites/babesiosis/data-statistics/index.html). Babesiosis is a zoonotic disease that is transmitted by tick vectors from infected animal reservoirs [1]. Most cases of babesiosis are caused by B. microti, which is primarily transmitted by Ixodes scapularis ticks from infected whitefooted mice from May to October in the Northeastern (NY, MA, CT, NJ, and RI) and upper Midwestern (WI and MN) US [1][2][3][4]14]. Sporadic cases have been caused by Babesia duncani in the West and Babesia divergens-like organisms in various parts of the US [2]. In Europe, most cases are due to Babesia divergens while cases due to Babesia venatorum and B. microti have been reported [3]. In Asia, cases due to B. venatorum, B. microti, Babesia crassa-like organism, KO1, and XXB/HangZhou have been reported [1].
Te mortality rate among hospitalized patients with babesiosis can be approximately 10% with a higher mortality rate among those who are immunocompromised or acquired infection through blood transfusion [1,3,15]. While there is no consensus on the defnition of severe babesiosis, severe babesiosis has been described as requiring hospitalization >2 weeks, admission to the intensive care unit >2 days, presence of splenic rupture, heart failure, respiratory failure, ARDS, or shock, the need for a red blood cell exchange transfusion, or death [16,17].
Severe babesiosis typically occurs in patients with one or more of risk factors including asplenia, HIV infection, immunosuppressive therapy, and age >50 years [1,3,15]. Our review of ARDS cases reveals similar fndings (Table 1). However, patients with advanced age or immunocompromised conditions tend to have comorbidities, which can infuence the severity of illness. In a study of 34 hospitalized patients with severe babesiosis in Long Island, NY, the average duration of parasitemia after initiation of treatment was 8.5 days (median, 12 days; range, 3-21 days) and a longer duration of parasitemia for ≥10 days was not associated with complicated babesiosis [5]. High-grade parasitemia is not a requisite for severe babesiosis or ARDS. Greater than 20% of severe babesiosis [5,6,17] and 37.5% (6/ 16 patients) of ARDS caused by babesiosis [6,[8][9][10][11][12][13] occurred in patients with parasitemia ≤1 percent (Table 1). Te studies indicate that the correlation between clinical severity and parasitemia is weak or none [6,15,18]. Our patient is another example of severe babesiosis with ARDS that occurred in the setting of low parasitemia. Further studies to shed light on risk factors for severe babesiosis or ARDS are needed.
ARDS is a potentially fatal respiratory condition with a mortality rate of 27-45% [7,19]. ARDS was the most common complication (20.6%) in the above study from Long Island, NY [5] and was the most common complication (8%) after congestive heart failure (10.9%) in a study of 139 hospitalized patients with babesiosis in the New York State [17]. ARDS evolves from early difuse alveolar-capillary damage characterized by alveolar-capillary permeability leading to alveolar edema to later fbro-proliferative and fbrotic phases if the patients survive [7,19]. Te Berlin defnition of ARDS refned from the 1994 American-European Conference Consensus defnition was developed by a panel of experts in 2011, which includes (1) within 1 week of a known clinical insult, or new or worsening respiratory symptoms, (2) bilateral opacities which are not explained by efusions, lobar or lung collapse, or pulmonary nodules, (3) respiratory failure not fully explained by cardiac failure or fuid overload, and (4) [7,19].
Te exact mechanism of ARDS caused by babesiosis is unknown. Sequestration of parasitized red blood cells (RBCs) leading to obstruction of the microvasculature of vital organs is the major pathogenesis of Plasmodium falciparum and Babesia bovis (a causative organism of bovine babesiosis) [1,20]. However, microvascular sequestration has not been demonstrated in human babesiosis due to B. microti [1]. For example, an autopsy of a splenectomized patient with B. microti infection with cerebral involvement revealed the absence of erythrocyte sequestration [21]. Te release of proinfammatory cytokines in patients with babesiosis may cause cellular damage and vascular leakage leading to ARDS [1]. It is possible that the destruction of babesia organisms after antibabesia therapy triggers a more intense infammatory response contributing to the development of ARDS [6,22]. Intriguingly, ARDS caused by malaria often occurs within a few days of starting antimalaria drugs analogous to ARDS caused by babesiosis [20].
Coinfections with additional pathogens that are transmitted by Ixodes scapularis including B. burgdorferi, A. phagocytophilum, Babesia miyamotoi, and Powassan virus can occur, resulting in further variation in clinical symptoms [23][24][25]. Coinfections of B. burgdorferi and babesiosis are the most common coinfections in Lyme disease-endemic areas in the US, accounting for more than 80% of coinfections [23][24][25]. Up to 40% of patients with Lyme disease have concurrent babesiosis, and two-thirds of patients with babesiosis have concurrent Lyme disease [23,25]. We contemplated a possibility of a coinfection of babesiosis and Lyme disease complicated by Jarisch-Herxheimer reaction to explain our patient's paradoxical worsening of symptoms shortly after the initiation of antibiotic therapy. Te Jarisch-Herxheimer reaction is a transient systemic reaction including fever, chills, rigors, headache, hypotension, and worsening rash, which typically occurs within 24 hours after the patients infected with spirochetes receive treatment for such infections [26]. However, ARDS as a result of a Jarisch-Herxheimer reaction associated with Lyme disease treatment has not been described contrary to another spirochetal disease, tickborne relapsing fever, which could potentially cause ARDS as a result of a Jarisch-Herxheimer reaction [26,27]. Furthermore, it is unusual for the initial positive IgM bands for Lyme disease to disappear within 3 months if it were a true case of Lyme disease while no additional gain of IgG bands may be explained by early antibiotic therapy [28,29]. Te presence of a transient false positive IgM response to B. burgdorferi during active babesiosis has been recently described, which could be due to polyclonal B cell activation triggered by babesiosis [30]. Taken together, we suspect that the initial Lyme disease test was a false positive due to immune activation from the babesiosis in this patient.
In conclusion, ARDS is a rare but major life-threatening complication of severe babesiosis. ARDS occurs more commonly after treatment for babesiosis is initiated. Te patient with babesiosis can rapidly develop ARDS despite initial stable respiratory status and low parasitemia burden. Further studies to identify the mechanism and risk factors for babesiosis-induced ARDS are warranted. Clinicians should have a high index of suspicion for concurrent tickborne diseases especially if the patient is found to have unusual fndings for babesiosis alone. Conversely, clinicians should be aware of the possibility of false positive IgM serology test results of other tick-borne diseases associated with active babesiosis.

Data Availability
No data were used to support the fndings of this study.

Consent
Authorization for publication of case study was obtained from the patient.

Conflicts of Interest
Te authors declare that they have no conficts of interest.