Aplastic anaemia following antibiotic use for urinary tract infection

Abstract

Aplastic anaemia is often associated with recent viral illnesses to include EBV and parvovirus along with certain medications such as anticonvulsants and sulfa containing antibiotics. We describe a case report of a female patient in her 70s who presented with pancytopenia after being treated with nitrofurantoin and ciprofloxacin for suspected urinary tract infection. She underwent an extensive workup to rule out alternative aetiologies of her pancytopenia to include a broad viral, autoimmune and malignancy evaluation which were unrevealing. Given her recent exposure to ciprofloxacin and nitrofurantoin and marrow recovery following removal of these agents, it was presumed that antibiotic exposure was the underlying cause of her aplastic anaemia.

Background

Aplastic anaemia is defined by pancytopenia that is associated with a hypocellular bone marrow without evidence of malignancy or dysplasia. Aplastic anaemia is a potentially life-threatening disease if not treated in a timely fashion due to sequalae of low haemoglobin (Hb), platelets and white cell count.¹ Seen in 1–7 per million, aplastic anaemia is a relatively rare disease.² The pathophysiological mechanisms that underly aplastic anaemia are not fully understood. Current understanding of causes can be broken down into three categories: direct marrow damage, immune-mediated response and predisposing genetic syndromes.¹ Direct marrow damage most commonly occurs from chemotherapy and radiation. However, it can be less commonly caused by a variety of agents, including benzene-containing compounds as well as thiazide diuretics, anticonvulsant medications such as carbamazepine, antithyroid agents such as methimazole, chloramphenicol and trimethoprim/sulfamethoxazole.^{3 4} Here, we present a unique case of a female patient in her 70s who presented with aplastic anaemia following antibiotic treatment with ciprofloxacin and nitrofurantoin. The pancytopenia resolved after withholding antibiotics and supporting with granulocyte colony-stimulating factor.

Case presentation

A female patient in her 70s with a history of metastatic ovarian cancer initially presented with dysuria concerning for a urinary tract infection (UTI). One month prior, a routine CBC demonstrated a white cell count (WCC) of 6800 x10^∧9/L with an ANC of 4100 x10^∧9/L, Hb of 10.7 g/L and platelet count (PLT) of 253 000/µL. The patient was previously found to have stage IIIa serous ovarian cancer in 2009, for which she underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and 12 cycles of carboplatin and paclitaxel approximately 10 years prior to her presentation. Genetic testing at the time of diagnosis revealed a pathogenic variant in the CHEK2 gene, specifically EX8_9del. Subsequently, a screening colonoscopy 4 years ago revealed a rectal polyp positive for metastatic adenocarcinoma consistent with her primary ovarian cancer, for which she received another six cycles of carboplatin and paclitaxel. At the time of her current presentation, there was good disease control of the patient’s ovarian cancer, and she had been on niraparib as maintenance therapy for approximately 24 months. Urinalysis testing was significant for cloudy, yellow urine negative for nitrites with a pH of 5.0, trace protein, 1+leucocytes and 4+bacteria. Given her symptoms and clinical suspicion for UTI, she was started on nitrofurantoin, and a urine culture subsequently returned positive for >100 000 CFU/mL of pan-sensitive Escherichia coli. Within 1 day of starting antibiotic therapy, she began to experience nausea, dizziness and nosebleeds. She called her physician and was told to discontinue her niraparib until resolution of her UTI. Despite this, her symptoms persisted, and she presented to a local emergency department 3 days later. At that time, the patient was noted to have a comprehensive metabolic panel notable for a mildly elevated alkaline phosphatase (138), BUN (27) and serum creatinine (1.07). A CBC was not performed at the time. As the patient continued to report malodorous, cloudy urine, her nitrofurantoin was discontinued and she was discharged with a 3-day course of ciprofloxacin to complete her treatment course. The patient subsequently developed worsening of her nosebleeds, as well as the onset of weakness, shortness of breath, bruising and mouth sores. This prompted her to return to the emergency department approximately 3 days later. Initial workup in the emergency department was notable for a WCC of 1800/µL with 94% lymphocytes with an ANC of 0/µL, Hb of 7.5 g/L w/a reticulocyte count of 0.21% and PLT of 2000x10^∧9/L. See figure 1 for a simplified representation of her medical history and presentation. Given the patient’s acute presentation, she was transfused two units of platelets and one unit of packed red cell count and was consequently transferred to our tertiary care medical centre for further workup of a possible underlying haematological malignancy.

Figure 1.

Timeline of patient events corresponding to drug administration (created by ASuresh). PLT, platelet; UTI, urinary tract infection; WCC, white cell count; CBC, complete blood count; G-CSF, Granulocyte colonoy stimulating factory.

Investigations

Iron studies were all within normal limits with no direct or indirect hyperbilirubinaemia. A peripheral smear was negative for blasts, myelocytes or promyelocytes and notable for normocytic normochromic anaemia with no spherocytes, schistocytes or reticulocytosis. The patient also underwent an extensive haematological workup to include D-dimer, fibrinogen, PT/INR panel as well as haptoglobin, and LDH, all of which were within normal limits. Further testing revealed normal vitamin B₁₂ and folate levels, as well as mildly elevated copper levels of 1.80 µg/mL (reference range: 0.75–1.45 µg/mL). Despite a lack of peripheral blasts, there was adequate suspicion for an acute leukaemia. The patient subsequently underwent a bone marrow biopsy, which demonstrated a markedly hypocellular bone marrow (5%–10%) with significant pan-myeloid hypoplasia and small lymphoid aggregates containing predominantly T cells. Normal immunophenotypic results were seen on flow cytometric testing of the bone marrow aspirate, with no monotypic B-cell population, phenotypically abnormal T-cell population or increase in blasts. Cytogenetic testing on the bone marrow specimen revealed a normal karyotype of 46 XX, but there were insufficient cells for a complete 20 cell analysis. A 40-gene myeloid sequencing panel was also negative. A CT scan of her chest/abdomen and pelvis did not demonstrate any new masses concerning for malignancy or lymphadenopathy. Further workup was notable for a negative infectious panel, including HIV, EBV, CMV and tickborne disease panel.

Differential diagnosis

Haematological malignancies, including acute leukaemias, lymphomas and myelodysplastic syndromes (MDS), viral and tickborne infections, nutritional deficiencies, and iatrogenic reactions leading to aplastic anaemia, were all considered as possible causes of the patient’s pancytopenia. The patient’s prior history of exposure to platinum-based chemotherapy 10 years ago also increases her risk of therapy-related myeloid neoplasms, specifically MDS and AML.⁵ There was no morphological evidence of dysplasia and no cytogenetic or molecular mutations were detected concerning for acute leukaemia or MDS on the bone marrow biopsy. Hypoplastic MDS was considered based on hypocellularity in the bone marrow but was deemed less likely than aplastic anaemia due to the absence of blasts and fibrosis, normal cytogenetics and absence of dysmegakaryopoiesis and dysgranulopoiesis.⁶ CT scan did not reveal any evidence of lymphadenopathy concerning for lymphoma. The patient’s known CHEK2 pathogenic variant is associated with an increased incidence of breast, colorectal, kidney and thyroid cancer, but not with any haematological malignancy.⁷ A broad infectious workup for HIV, EBV, CMV and tickborne infections including Lyme disease was unremarkable. Her diet did not raise any suspicion for nutritional deficiency, and this was further supported by normal vitamin B₁₂ and folate levels. While copper deficiency can contribute to pancytopenia, her copper levels were mildly elevated rather than reduced. Serum zinc levels were not obtained due to the low likelihood of zinc deficiency or toxicity. Given her recent exposure to antibiotics, we concluded that the most likely cause of her aplastic anaemia was recent exposure to nitrofurantoin or ciprofloxacin. See figure 2 for a summary of the differential diagnosis and diagnostic evaluation corresponding to the potential mechanisms of pancytopenia.

Figure 2.

Potential mechanisms of pancytopenia and diagnostic workup (created by ASuresh). MDS, myelodysplastic syndromes; EBV, Ebstein Bar Virus; CMV, cytomegalovirus; DIC, disseminated intravascular coagulation; LDH, lactate dehydrogenase; MPN, myeloproliferative neoplasm.

Treatment

Since the patient met the criteria for a diagnosis of severe aplastic anaemia, we had to decide whether to start standard treatment with antithymocyte globulin, cyclosporine and eltrombopag, or to delay this treatment and give the patient’s bone marrow time to recover after the presumed insult resulting from the antibiotic use. We initially decide to defer treatment while providing supportive care and monitoring her CBC. Later, based on the patient’s desire to return home as soon as possible, G-CSF was started on day 3 of admission to reduce risk of infection and hospital length of stay.

Outcome and follow-up

Fortunately, the patient’s WCC count and ANC started to rise on day 5 of admission, 2 days after starting G-CSF. G-CSF was continued for a total of 7 days, until she was discharged from the hospital on day 9. At the time of hospital discharge, the patient had a WCC of 6400 x 10^∧9/L with an ANC of 2160 x 10^∧9/L, Hb of 8.2 g/L and PLT of 186 000 x 10^∧9/L. At her most recent follow-up, 99 days following discharge, she continues to demonstrate stability in her CBC (WCC 7700 x 10^∧9/L with an ANC of 3830 x 10^∧9/L, Hb 10.9 g/L, PLT 250 000 x 10^∧9/L) and has not had a repeat bone marrow biopsy due to lack of clinical necessity. The patient’s niraparib has not been restarted since hospital discharge.

Discussion

Drug-induced aplastic anaemia is a diagnosis of exclusion. Based on the absence of other infectious or haematological causes in this case and the timing of onset of pancytopenia in close proximity to antibiotic use, we identified drug-induced aplastic anaemia as the most likely cause of the patient’s temporary aplastic bone marrow. In addition, there have been isolated case reports with each ciprofloxacin-induced and nitrofurantoin-induced aplastic anaemia.^8–10 In these cases, rapid bone marrow depression was seen within 2 weeks after antibiotic initiation for a UTI similar to our patient. Bone marrow recovery is not always observed following antibiotic discontinuation and fatal reactions have been reported.^{8 9}

Another medication we strongly considered was her poly-ADP ribose polymerase inhibitor (PARPi) niraparib, which has been associated with pancytopenia and even increased rates of MDS. However, we ultimately thought this was less likely since she had tolerated niraparib well for 2 years, with regular CBC monitoring during that time only showing a mild and consistent anaemia. There are additionally no known drug interactions between niraparib, ciprofloxacin and nitrofurantoin. According to a cross-sectional study of 194 serious cases of pancytopenia following PARPi use, the median latency period of pancytopenia was 1.6 months after first PARPi exposure, with a range between 0.2 and 29.9 months.¹¹ While we cannot rule out the PARPi causing this delayed idiosyncratic reaction, after weighing the risks of recurrent aplasia and the benefits of extended control of her metastatic ovarian cancer, we felt comfortable holding the PARPi in the outpatient setting. She is currently not taking the PARPi.

Classic aplastic anaemia is usually thought of as a potentially life-threatening bone marrow failure disorder, characterised by immune destruction of the haematopoietic stem cells.¹² Standard treatments involve regimens designed to suppress this autoimmune response, and thereby stop the attack on stem cells.¹² However, medications, even common ones, can cause aplastic anaemia, although the mechanism of whether this is due to direct toxicity, triggering a temporary immune response through antigenic mimicry, or differences in host drug metabolism, is unknown.^{12 13} This case report serves as a reminder of the many serious and idiosyncratic side effects that commonly prescribed drugs can have, which should be considered when patients present with unusual conditions. In this case, withholding the suspect medications and providing supportive G-CSF spared the patient the potential toxicity of treatment for classic aplastic anaemia.

Learning points.

• Patients presenting with pancytopenia require an extensive workup to rule out malignancy and infectious disease as potential causes of new-onset aplastic anaemia.

• Antibiotics, to include nitrofurantoin and ciprofloxacin, may be the causative agent in newly diagnosed aplastic anaemia.

• Antibiotics may induce aplastic anaemia either through direct toxicity to the bone marrow or through a temporary immune response as a result of antigen mimicry.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).