Key-words:
Autoimmune hemolytic anemia - ceftriaxone - direct antiglobulin test - hemolytic anemia
- piperacillin–tazobactam
Introduction
Autoimmune hemolytic anemia (AIHA) is the destruction of red blood cells due to autoantibodies
formation secondary to immune system malfunction. It has an estimated incidence in
adults of 1–3/100,000/year and a mortality rate of 11%.[[1]],[[2]],[[3]] It can be idiopathic (primary) or acquired (secondary). The acquired form of AIHA
has several etiologies, including drugs, infections, autoimmune diseases, and lymphoproliferative
disorders.
Drug-induced immune hemolytic anemia (DIIHA) is rare, occurring in about 1 per million
of the population.[[1]] More than 130 drugs have been reported to induce antibody formation, causing hemolysis.[[3]],[[4]],[[5]],[[6]] They are classified into drug-dependent antibodies and drug-independent antibodies.
The most common antibiotics reported to be associated with drug-dependent antibodies
are cephalosporin and penicillin.[[3]],[[5]],[[7]],[[8]],[[9]],[[10]]
The author reports two rare cases of DIIHA secondary to ceftriaxone and piperacillin–tazobactam
used in patients diagnosed with community-acquired pneumonia and percutaneous endoscopic
gastrostomy site infection, respectively.
Case Reports
Case 1
A 59-year-old female with a medical history of hypertension presented to the hospital
with a history of high-grade fever for 4 days duration associated with chills, fatigue,
dry cough, and shortness of breath (SOB) on mild exertion. There was no history of
wheezes. Normal bowel and bladder function. Surgical history included appendectomy
and lower cesarean section. Medication history included bisoprolol. There was no history
of allergies, recent travel, sick contact, or smoking. Her vital signs on initial
presentation: Heart rate was 68 beats/min, blood pressure 115/67 mmHg, temperature
38.7°C, and respiratory rate was 18 breaths/min. In the general examination, the patient
was in stable general condition. On chest examination, there was decreased air entry
in the right lower lobe with dullness to percussion and increased vocal fremitus.
Other systemic examinations were within normal limits.
The initial blood test showed a white blood count of 10.08 × 10/ccm with a left neutrophilic
shift, hemoglobin 101 g/L, platelets of 285 × 10/cmm, and C-reactive protein 639 mg/L.
Blood film on admission was reported to be normal. Chest X-ray showed patchy consolidation
in the right lower lobe. The patient was managed as a case of community-acquired pneumonia
and started on ceftriaxone and azithromycin. On day 2, the patient developed worsening
SOB requiring 3 L oxygen via nasal cannula to maintain oxygen saturation above 92%.
Her arterial blood gas analysis showed hypoxemia, and her electrocardiogram (ECG)
revealed a normal sinus rhythm. Serum D dimer level was abnormally high at 2.25 ug/mL;
however, a normal computed tomography angiography excluded pulmonary embolism. The
coagulation profile and fibrinogen level were normal. Repeat laboratory investigations
did not show any significant abnormalities, but improvement in inflammatory markers.
Mycoplasma IgM and Legionella urine antigen were negative. Blood and sputum cultures
were negative. On day 5, hemoglobin dropped to 71 g/L, and platelets result was 402
× 10/cmm.
No evidence of any active bleeding was observed. On day 6, anemia workup showed elevated
lactate dehydrogenase (LDH), low haptoglobin, elevated reticulocyte counts, and a
peripheral blood smear was suggestive of hemolytic anemia. The direct antiglobulin
test was positive for IgM, IgG, and C3d. Mycoplasma pneumonia associated hemolytic
anemia was ruled out by a negative mycoplasma IgM test. Patient had normal levels
of Glucoose-6-phophate dehydrogenase. Ceftriaxone was stopped on day 7. Following
hematology consultation, the patient was initiated on low-dose steroids. The patient
did well afterward and was weaned off oxygen. Her renal function was normal, and there
was no evidence of acute cardiac events. Repeat lab tests showed that hemoglobin was
stable at 76 g/L. The patient did not require a blood transfusion. She was discharged
on day 9 of the hospital stay. Patient was followed-up 3 weeks from day of discharge.
Repeated laboratory investigations showed normal levels of inflammatory markers and
hemoglobin of 93 g/L [[Figure 1]]. Also, the peripheral blood smear did not show any evidence of hemolysis. The patient
was in stable general condition with no active complaints.
Figure 1: Hemoglobin level during the hospital stay and 1-month postdischarge. The onset of
symptoms, hemolysis, and recovery are highlighted
Case 2
A 97-year-old male presented to the hospital with a high-grade fever for 1-day duration
associated with pus discharge from the gastrostomy feeding tube site, cloudy urine,
and reduced physical activity. The review of other systems was negative. He had a
medical history of hypertension, ischemic heart disease, atrial fibrillation, mechanical
mitral valve, cerebrovascular accident, chronic kidney disease, and iron-deficiency
anemia. His medication history includes warfarin, aspirin, bisoprolol, ferrous fumarate,
levothyroxine, omeprazole, rosuvastatin, and tamsulosin.
His vital signs on initial presentation: Heart rate was 71 beats/min, blood pressure
103/55 mmHg, temperature 38.6°C, and the respiratory rate was 20 breaths/min; on examination,
nothing significant apart from erythema around the gastrostomy tube site with pus
discharges. His laboratory investigations showed normal white blood cell (WBC) count
with a left neutrophilic shift, C-reactive protein (CRP) 138 mg/L, hemoglobin 9 g/L,
and international normalized ratio of 2.68. His most recent blood film was reported
normal with no evidence of dysplastic changes or leukemic cells. The patient had mild
renal impairment secondary to dehydration. The patient was empirically started on
piperacillin–tazobactam and received intravenous hydration. The patient responded
well to treatment, the renal function returned to baseline, and his inflammatory markers
were trending down. However, on day 5 of hospital stay, the patient required 1 L oxygen
therapy for mild SOB, but no evidence of a drop in oxygen saturation. Furthermore,
his urine was dark and black. Repeat laboratory investigations showed WBC 11.48 ×
10/cmm, hemoglobin 86 g/L, platelets of 285 × 10/cmm, increased reticulocytes count,
mild renal impairment, and and CRP 35 mg/L. His coagulation profile showed an INR
2.68, PTT 55s, PT 32s, and Fibrinogen 6g/L. Patient is on warfarin for underlying
atrial fibrillation. ECG and chest X-ray did not show any new acute pathology. Anemia
workup showed elevated LDH, low haptoglobin, indirect hyperbilirubinemia, and direct
antiglobulin test (DAT) positive for IgG. His Glucoose-6-phophate dehydrogenase level
was normal. Peripheral blood smear was suggestive of hemolytic anemia. The antibiotic
therapy was stopped as it was only drug newly started that can be associated with
hemolytic anemia. The patient was managed conservatively; he did not require blood
transfusion or other treatments. The patient was observed in the hospital for 2 weeks.
He was weaned off oxygen entirely, and all other associated symptoms subsided. His
renal function returned to normal baseline, and inflammatory markers resolved. Hemolytic
workup showed gradual improvement with first marker to normalize was the indirect
bilirubin. The patient did well after discharge, and a repeat hemoglobin level after
three weeks showed a result of 90 g/L [[Table 1]].
Table 1: Results of the hematological investigations of case 2
Discussion
DIIHA is a relatively uncommon disorder reported in several case reports in both children
and adults.[[9]] It can be unnoticed, asymptomatic, or mild in severity. Other cases have been reported
to have poor outcomes associated with multiple organ failure and even death.[[3]],[[10]] Acute renal failure has been reported as a common complication associated with
DIIHA,[[9]],[[10]] Multiple drugs have been mentioned in the literature to cause immune hemolysis,
and the most common antibiotics are cephalosporin and penicillin.[[3]],[[5]],[[6]],[[8]],[[9]],[[10]] These are widely used antibiotics for various medical conditions. The time of onset
of symptoms in people prone to develop DIIHA secondary to antibiotics varies. It was
reported that the time to onset of symptoms from penicillin-induced hemolytic anemia
could range from 1 to 2 weeks, and it can also extend up to 1 month.[[5]] In our case reports, hemolysis was identified after 2 days in the first case secondary
to ceftriaxone and after 5 days in the second case report secondary to piperacillin-tazobactam.
Different mechanisms have been mentioned in the literature to be involved in DIIHA;
they are drug-induced antibodies and nonimmunological protein absorption.[[6]],[[10]],[[11]] Ceftriaxone and piperacillin–tazobactam lead to immune hemolytic anemia by forming
drug-dependent antibodies. The presence of the drug in vulnerable people leads to
the production of antibodies that bind to erythrocytes and causes hemolysis. Drug-dependent
antibodies can be further classified into penicillin-type reaction and immune complex-type
reaction. Penicillin combines covalently with erythrocyte membrane proteins forming
a penicillin coated red blood cells (RBC). In the presence of IgG penicillin antibody,
the antibody will attach to the penicillin coated-RBC which will be cleared up by
macrophages and lead to hemolysis. In our case report, the second patient DAT result
was positive for IgG. Ceftriaxone causes immune-complex type reaction by the formation
of mostly IgM-type antibodies that lead to complement-mediated intravascular hemolysis.
DAT in ceftriaxone induced immune hemolytic anemia is usually positive for C3, IgM,
and in some cases also for IgG.[[3]],[[6]],[[9]],[[10]],[[11]],[[12]] This was identified in the first patient in our case report.
Laboratory tests that can aid in the diagnosis include complete blood count, lactate
dehydrogenase, haptoglobin, indirect bilirubin, urine dipstick, reticulocyte count,
peripheral blood smear, and DAT. Serological tests can be performed to confirm the
diagnosis, but this requires a specialized laboratory, and it may take a week to have
the result back.[[6]],[[12]] However, in all cases, discontinuation of the antibiotic and maintaining close
monitoring of the clinical status is the mainstay of treatment. Blood transfusion
can be considered if the patient is symptomatic and hemoglobin drops below 7 g/L.
Other treatment methods include steroids, intravenous immunoglobulin, and plasmapheresis.[[1]],[[6]],[[8]],[[12]]
In both the cases reported here, the onset of symptoms was within the 1st week of
initiating antibiotics. The main symptom observed in both patients was SOB, which
can be attributed to symptomatic anemia. One of the patients had acute renal impairment,
which is commonly associated with DIIHA. The mainstay of treatment once DIIHA is highly
suspected is to hold the culprit drug and to have Hematology team on board. The duration
of monitoring in hospitals may differ among people as it will depend on the clinical
status and other associated medical conditions. The main factors determining the severity
are the patient's clinical status, hemoglobin level, and associated complications
secondary to hypoperfusion. It is crucial to report the side effect on the patient's
chart to avoid re-exposure. Moreover, patients should be educated about the associated
complication and be followed within a month with routine labs and general checkups.
Conclusions
Antibiotic-induced hemolytic anemia is a rare adverse reaction that can develop within
48 h of starting antimicrobial treatment. Hemolytic workup should be considered in
all patients with new-onset SOB or change in urine color immediately after the initiation
of antibiotics. Physicians should be vigilant, and early diagnosis is crucial to prevent
severe outcomes.
Author's contribution
Single author.
Compliance with ethical principles
Ethical approval was obtained from Research Ethics Committee at Sheikh Shakhbout Medical
City. The reported information cannot lead to the identification of the involved individuals.
Reviewers:
Ashraf Elghul (Abu Dhabi, UAE)
Adel Al.Tawaty (Benghazi, Libya)
Samir Kahwah (Columbus OH, USA)
Editors:
Salem A Beshyah (Abu Dhabi, UAE)
Elmahdi A Elkhammas (Columbus OH, USA)
