Lyme disease as a rare trigger for autoimmune hemolytic anemia

Abstract

Introduction

Lyme disease, caused by Borrelia burgdorferi, is a zoonotic infection affecting the skin, nervous system, joints, and heart. Diagnosis relies on clinical history, symptoms, and a two steps serologic test confirmed by Western Blot. Although it frequently affects other systems, data on the haematological involvement spectrum of Lyme disease appears to be limited to case reports, and there are few studies that clearly demonstrate its relationship with haemolytic anaemia. This case highlights Lyme disease presenting with autoimmune hemolytic anemia (AIHA) and thrombocytopenia.

Case

A 47-year-old woman with alcoholic cirrhosis (Child-Pugh B, Model for End-Stage Liver Disease (MELD) 9) presented with leg swelling, jaundice, and deep vein thrombosis. Laboratory evaluation showed severe anemia, thrombocytopenia, elevated lactate dehydrogenase (LDH), indirect hyperbilirubinemia, and acute kidney injury. Differential diagnoses, including disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, paroxysmal nocturnal hemoglobinuria, and spur cell anemia and other source of infection were excluded. Coombs-positive hemolysis, normal nutritional markers and peripheral blood smear confirmed autoimmune hemolytic anemia (AIHA). Despite prednisone therapy, thrombocytopenia worsened and neuropathic symptoms developed. Given recent European travel, Lyme disease was suspected and confirmed by Borrelia burgdorferi IgM and Western Blot. Following ceftriaxone and doxycycline, hemoglobin improved without transfusion, platelets normalized, and neuropathic symptoms regressed, highlighting Lyme disease as a rare cause of AIHA.

Conclusion

Lyme disease, though uncommon, may present with autoimmune hemolytic anemia, emphasizing the need to consider this rare association in differential diagnosis when clinical suspicion arises.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12879-025-12486-x.

Introduction

Lyme disease, a zoonotic infectious disease caused by spirochetes called Borrelia burgdorferi (Bb). Diagnosis is based on history, symptoms and a two-step serologic test [1, 2]. Positive immune serology is confirmed by Western Blot. Lyme disease (LD) usually presents initially with an erythematous rash known as erythema migrans (EM). If left untreated, Lyme disease can affect the heart in about 4–8% of patients, cause neurological symptoms in 11%, and lead to arthritis in 45–60% [2]. Even with appropriate antibiotic treatment, some patients may continue to experience persistent symptoms such as fatigue, cognitive impairment, and pain. LD is classified as stage 1 (early localized), stage 2 (early disseminated) and stage 3 (late persistent) [2]. Borrelia burgdorferi sensu lato (Bb), the most common tick-borne infection, has a global distribution. Seroprevalence rates are notably high, particularly in Central Europe, Western Europe, and Eastern Asia [3]. Although it frequently affects other systems, data on the haematological involvement spectrum of Lyme disease appears to be limited to case reports, and there are few studies that clearly demonstrate its relationship with haemolytic anaemia. This case report presents Lyme disease presenting with autoimmune haemolytic anaemia, and thrombocytopenia, which differs from the classic clinical manifestation.

Case report

A 47-year-old woman with a known diagnosis of alcoholic liver cirrhosis (Child-Pugh B, MELD 9) was admitted to the emergency department with complaints of swelling in the left leg, pain in the calf region and jaundice which had been present for 1 month and gradually worsening.

In the assessment carried out during the emergency admission, deep vein thrombosis was detected on venous doppler ultrasound of the left lower extremity and laboratory tests revealed Hemoglobin (Hb) 4. 2 g/dl, hemotocrit 13.6%, white blood cell (WBC) 30.85 × 10^9 /L (neutrophil: 24.39 × 10^9 /L, lymphocyte: 3.94 × 10^9 /L, platelet: 110 × 10^9 /L, c-reactive protein: 28 mg/L and d-dimer: 13105 ng/ml, total bilirubin: 5.90 U/l, indirect bilirubin: 3.77 U/l, LDH: 465 U/l, international normalized ratio (INR): 2.01, fibrinogen 1.66 g/L (normal renge 2 to 4 g/L), urea 60 mg/dl, creatinine 2.30 mg/dl (basal creatinine: 0.70 mg/dl) and disseminated intravascular coagulation (DIC) was not considered due to the observation of rare schistocytes in the peripheral smear, which was examined with a prediagnosis of DIC. In the patient diagnosed with cirrhosis, spontaneous bacterial peritonitis and possible infectious processes were not included in the differential diagnosis, as no ascites was detected on physical examination or imaging studies, and no other infectious focus was identified on physical examination. She was admitted to the general internal medicine service to deterimine the etiology of thrombophilia, acute renal injury and anemia. Investigations into the aetiology of the patient’s thrombosis ruled out antiphospholipid syndrome, thrombotic thrombocytopenic purpura, paroxysmal nocturnal haemoglobinuria, and hereditary thrombophilia (Supplement 1). The patient was assessed as hypovolaemic on admission and, due to their response to intravenous isotonic saline, her current acute kidneyl injury was assessed as prerenal.

In tests sent to determine the aetiology of anaemia in a patient requiring transfusion due to severe anaemia, haptoglobulin < 0.058 g/dl, absolute reticulocyte count 2 × 103/ml, reticulocyte index 0.80, pre-transfusion direct coombs immunoglobulin G (ıg G) pozitive, Cd3 and indirect coombs negative, nutritional parameters were normal. In the peripheral smear, poikilocytosis in the erythrocytic series, acanthocytes (4%), schistocytes (2%, 1 schistocytes were seen in 3 out of 10 fields.), platelet count compatible with 100–130 × 10^9 /L and no atypical features were observed in other cell series ( Fig. 1A and B; Tables 1 and 2).

Fig. 1.

A/B. Peripheral Blood Smear; poikilocytosis in the erythrocytic series, acanthocytes (4%), schistocytes (2%)

Table 1.

Hematologic surveillance

	At Administration	Day. 0 steroid treatment	15 th day of steroid treatment	3 rd week of dual antibiotherapy	At Discharge
RBC count, million cells/mm3	1,09	1,86	2,36	2.50	2.57
Hemoglobin, g/dL	4.2	6.2	8.9	9.230	9.1
Hematocrit,%	13.6	19.3	26.3	30.2	29.4
Platelet count, x 10^9 /L	132	129	30	90	174
WBC count, cells/mm3	30,85	27,63	22,25	11.81	10.79
Segments,%	79.0	78.7	17.81	67.3	61.4
Lymphocytes,%	3.94	10.2	10.6	22.3	21.8
Eosinophils,%	0.28	1.8	2.2	1	2
Basophils,%	0.08	0.6	0.2	0.3	0.9
Monocytes%	7	8.7	7	9	8
MCV fL	124.8	103.8	111.4	120.8	114
MCH pg/cell	28.5	33.3	37.7	36.8	35.4
Haptoglobulin, g/dl	< 0.058	< 0.058	< 0.058	NA	< 0.058
Absolute Reticulocyte count x103/ml	2	5.3	4.9	NA	3.3
Reticulocyte index	0.80	2.11	3.24	NA	3.3
Direct coombs IgG/C3d	NA	+/-	-/-	NA	-/-
Indirect coombs	-	-	-	NA	-
Serum iron, mcg/dl	53	NA	148	NA	NA
TS,%	29	NA	99	NA	NA
TIBC, mcg/dl	181	NA	149	NA	NA
Ferritin, ng/ml	977	NA	1312	NA	487
Vitamine B12, pg/ml	1311	NA	1077	NA	NA
Folic asit, ng/ml	5.63	NA	7.68	NA	NA

Abbreviations: RBC: red blood cell, WBC: white blood cell, MCV: mean corpuscular volume, MCH: mean corpuscular hemoglobin, NA: non-avaliable, +: positive test result, -: negative test result, IgG: Immunoglobulin G, TS: transferrin saturation, TIBC: total iron binding capacity

Table 2.

Broad biochemistric surveillance

	At Administration	Day. 0 steroid treatment	15 th day of steroid treatment	At Discharge
Urea nitrogen, mg/dL	60	19	30	21
Creatinine, mg/dL	2.3	0.3	0.32	0.40
Sodium, mmol/L	126	126	134	136
Potassium, mmol/L	5.3	4	3.5	3.6
Calcium, mg/dL	8.9	7.8	8.8	8.2
Magnesium, mg/dl	1.43	1.5	1.41	1.62
Blood glucose, mg/dL	126	110	102	104
Total protein, g/dL	80.5	68.7	75.7	63.2
Albumin, g/dL	32.9	30.7	34.4	31.5
Total bilirubin, mg/dl	5.9	14.3	12.6	4.43
Indirect bilirubin, mg/dl	3.77	10.31	9.84	1.8
AST, IU/L	97	98	74	44
LDH, U/L	465	737	751	390
ALT, IU/L	23	27	58	18
GGT, IU/L	290	139	189	131
ALP, IU/L	113	77	136	102
INR	2.01	2.41	1.94	NA
TG, mg/dl	69	NA	NA	NA
LDL, mg/dl	100	NA	NA	NA
Total kolestrol,/mg/dl	202	NA	NA	NA

Abbreviations: AST: Aspartate aminotransferase, LDH: Lactate dehydrogenase, ALT: Alanine aminotransferase, GGT: Gamma-glutamyltransferase, ALP: Alkaline phosphatase, INR International normalized ratio, TG: iglyceride, LDL: Low- Density Lipoprotein, NA: non-avaliable

It was evaluated as autoimmune hemolytic anemia in the foreground due to the accompanying elevated hemolysis parameters (such as LDH, indirect bilirubin) and direct coombs positivity. In this case of secondary alcoholic liver cirrhosis presenting with acute haemolysis, Zieve syndrome was not considered due to normotriglyceridaemia and direct Coombs IgG positivity in the investigations performed. In a patient with 3% acanthocytes/Spurr cells in the peripheral smear, Spurr cell anaemia was also not considered due to direct Coombs positivity. Therefore, autoimmune hemolytic anemia was considered and prednisone 40 mg/day was started on the 10th day of admission.

During the clinical follow-up, the patient’s laboratory tests showed a decrease in platelet count to 30 × 10^9 /L, a newly developed drop foot in the left lower extremity and nocturnal neuropathic pain in the same extremity. In the patient’s existing condition, small vessel vasculitis and autoimmune pathologies were included in our differential diagnosis, but we ruled them out with the immunoserological evaluation performed (Supplement 1). In a case being monitored with cortisone treatment due to autoimmune haemolytic anaemia, the patient’s recent travel history to Switzerland 32 days prior to the onset of symptoms led us to consider Lyme disease in our differential diagnosis, despite the absence of typical lesions and known tick exposure, due to the development of new neuropathic pain worsening at night and worsening thrombocytopenia. Therefore, Borrelia burgdorferi immunoblot IgG and IgM tests were performed (Supplement 2). The immunoblot B. burgdorferi IgM test was positive, and a confirmation test with Western Blot (WB) was subsequently performed. The WB results revealed IgM weak positivity in the OspC Bg, Bb, and Ba bands, as well as IgG positivity in the OspC band and weak positivity in the VIsE-Bb band.

The patient was accepted as Early Disseminated Lyme Diease and ceftriaxone was started. Doxycycline was added to the treatment upon clinical response in the second week of treatment. Under dual antibiotic treatment, platelet count increased to 176 × 10^9 /L and neuropathic pain decreased but the drop foot finding persisted during clinical follow up settings. It was observed that the low foot clinic improved in the 3rd month after discharge. The patient who received prednisone 1 mg/kg for autoimmune hemolytic anemia did not need erythrocyte suspension replacement in the 2nd week of steroid treatment and hemoglobin level increased to 8.9 g/dl. In the patient whose Lyme treatment was completed and steroid was titrated and discontinued during follow-up, hemoglobin reached 10 g/dl.

Discussion

Lyme disease is a tick-borne infection with multi-organ involvement, especially the skin, nervous system, musculoskeletal system and heart [1, 2]. Borrelia burgdorferi sensu lato (Bb) infection, the most frequent tick-transmitted disease, is distributed worldwide. Autoimmune hemolytic anemia (AIHA) is a disease characterized by the breakdown of erythrocytes and anemia as a result of the patient producing antibodies against their own erythrocytes. This condition, which is idiopathic in most patients, can be secondary to some autoimmune, infectious diseases and hematologic/nonhematologic malignancies [4, 5]. However, although data on lyme-associated hematologic involvement are scarce, other possible etiologic causes were excluded by diagnostic workup in this case (Supplement 1).

There are no studies that clearly demonstrate the relationship between Lyme disease and secondary anemia. Hemolytic anemia is not included in the classical picture of Lyme disease, and in the literature review, there are studies demonstrating Lyme-related anemia and thrombocytopenia in animal and human models [6, 7]. However, there are case report studies showing that hemolytic anemia develops in the presence of co-infection with babesseos [8, 9]. In addition to babesiosis coinfection, Ixodes ticks are also capable of simultaneously transmitting other human pathogens, such as Anaplasma phagocytophilum and Ehrlichia species [10]. Epidemiological data indicate that as many as 40% of individuals with Lyme disease may have concurrent babesiosis and up to 13% may have concurrent human granulocytic anaplasmosis (HGA) [10]. In contrast, such coinfections are less frequently reported in Europe than United States of America, where single infections with Babesia spp. or A. phagocytophilum are themselves relatively uncommon [10, 11]. In our case, the exposure occurred in Europe, where coinfection is not primarily considered; however, since babesiosis is the most common accompanying infection in such settings, a thin peripheral smear was performed to rule out concurrent infection, and babesiosis was found to be negative. PCR and serological tests for babesiosis were not performed as they were not available in our center.

The thrombocytopenia observed in this case may be a component of cirrhosis, as well as Lyme-associated thrombocytopenia, as seen in the case study reported in the literature [6]. In the same report of 6 cases of lyme-associated thrombocytopenia, it is emphasized that improvement in platelets was more pronounced in patients given doxycycline (doxycycline in 2 cases, prednisone in 1 case, ceftriaxone in 3 cases) compared to other treatment options [6]. In our case, we added doxycycline to the treatment in the second week of ceftriaxone, and similarly to the previous study, the platelet count rose from 30 × 10^9/L to 176 × 10^9/L.

Previous studies have shown that Lyme borreliosis (Lb) increases autoimmunity, and this may explain Lyme-associated anaemia/thrombocytopenia. Several case reports have described the association between LB and the development of autoimmune diseases such as systemic lupus erythematosus, scleroderma, Guillain-Barre syndrome and Multiple sclerosis [12–14]. Although the exact mechanism underlying cytopenias secondary to Lyme disease in human models remains unclear, several processes—such as molecular mimicry, epitope spreading, bystander activation, original antigenic sin, polyclonal activation of B and T cells, and apoptosis of antigen-presenting cells—have been implicated in the development of autoimmunity [15]. Furthermore, some studies highlight the role of T regulatory (Treg) cells, Th17 immune responses, and IL-23 levels in the pathogenesis of post-treatment Lyme disease [16]. Findings from the literature support that lyme-associated increased autoimmunity may play a role in the development of autoimmune hemolytic anemia.

As a conclusion, although studies have been conducted showing the association between thrombocytopenia, chronic disease anemia, and Lyme disease, it is difficult to demonstrate this correlation, particularly with regard to autoimmune hemolytic anemia. As demonstrated in our multidisciplinary case, we believe that Lyme disease should be considered in the differential diagnosis of autoimmune hemolytic anemia, even if it is rare, when there is a suspicious history.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

ADAMSTS-13

A Disintegrin and Metalloproteinase with a Thrombospondin Type 1 Motif, Member 13

AFAS

Antiphospholipid Antibody Syndrome

AIHA

Autoimmune Hemolytic Anemia

AKI

Acute Kidney Injury

ANA

Antinuclear Antibody

ANCA

Anti-neutrophil Cytoplasmic Antibody

anti-DsDNA

Anti-Double Stranded DNA

DIC

Disseminated Intravascular Coagulation

DVT

Deep Ven Trombosis

hb

Hemoglobin

Ig

Immunoglobulin

LDH

Lactate Dehydrogenase

MELD

Model for End-Stage Liver Disease

MTHFR

Methylenetetrahydrofolate reductase

OspC Ba

Outer surface protein C of Borrelia afzelii

OspC Bb

Outer surface protein C of Borrelia burgdorferi

OspC Bg

Outer surface protein C of Borrelia garinii

PNH

Paroxysmal Nocturnal Hemoglobinuria

SLE

Systemic Lupus Erythematosus

TTP

Thrombotic Thrombocytopenic Purpura

VIsE-Bb

Variable major protein-like sequence expressed of Borrelia burgdorferi

Author contributions

Concept: All; Design: All; Data collection or processing: All; Analysis or Interpretation: All; Literature search: All; Writing: All; Approval: All. Acknowledgments and Conflicts of Interest: The authors declare no conflicts of interest.

Data availability

Not applicable.

Declarations

Ethics and informed consent

Written informed consent was obtained from patient for the publication of this case.

Consent for publication

The case is being handled in 2022, and it was learned that the patient died on 03.2025 due to complications of cirrhosis during a screening conducted in the system for approval. Therefore, written permission for publication was obtained from the patient’s relatives.

Financial support and sponsorship

None.

Competing interests

The authors declare no competing interests.