Toxic agranulocytosis following nitazoxanide treatment for norovirus diarrhea in a kidney transplant recipient: A case report and review of literature

Abstract

BACKGROUND

In France, nitazoxanide is available through compassionate use authorization, as there is no summary of product characteristics for this medication. However, it has been marketed in the United States for several years, with evidence supporting its use in the treatment of chronic norovirus infections in immunocompromised individuals. Due to its limited use, data on the efficacy and safety of this drug remain sparse.

CASE SUMMARY

We report the case of a 79-year-old immunocompromised patient, a renal transplant recipient undergoing treatment with mycophenolate mofetil and tacrolimus, who developed toxic agranulocytosis, as absolute neutrophil count dropped from 2.93 G/L to 0.09 G/L within 17 days following the introduction of nitazoxanide for the treatment of chronic diarrhea caused by norovirus infection. Clinical and laboratory findings suggest a toxic mechanism, most likely attributable to nitazoxanide.

CONCLUSION

This case highlights the potential of nitazoxanide to induce dose-dependent toxic agranulocytosis. While this adverse effect does not necessarily contraindicate reintroduction of the drug, it underscores the necessity for close hematological monitoring in such cases.

Key Words: Agranulocytosis; Neutropenia; Nitazoxanide; Norovirus; Iatrogeny; Case report

Core Tip: Nitazoxanide is a thiazolide compound. The Food and Drug Administration has approved it for the treatment of Giardia intestinalis and Cryptosporidium parvum infections in immunocompromised patients aged 12 years or older. In immunocompromised patients, nitazoxanide use for chronic Norovirus diarrhea has been reported and appears promising, including in solid organ transplant recipients. However, the drug is not yet approved for this indication. We herein report on a patient for which nitazoxanide induced a dose-dependent toxic agranulocytosis.

INTRODUCTION

Norovirus is a positive-sense, single-stranded RNA virus belonging to the Caliciviridae family. Its primary mode of transmission is fecal-oral, occurring either directly or indirectly. Norovirus is the leading cause of acute gastroenteritis across all age groups and the most common etiological agent in outbreaks of foodborne illnesses[1]. In immunocompetent individuals, infection typically resolves spontaneously and rapidly. However, vulnerability due to frailty or immunosuppression predisposes individuals to chronic norovirus infections, characterized by prolonged diarrhea[2]. Solid organ transplant (SOT) recipients are particularly susceptible to such infections.

Management of chronic norovirus infections in SOT patients remains poorly standardized. Treatment strategies are largely empirical and include reducing immunosuppression when feasible[3] or replacing calcineurin inhibitors with everolimus, which possesses antiviral properties[4,5]. The use of intravenous immunoglobulins has also been explored, with some evidence suggesting it may aid in viral clearance[6].

Nitazoxanide is a thiazolide compound. Its chemical structure is 2-acetyloxy-N-(5-nitro-2-thiazolyl) benzamide. The benzamide structure resembles niclosamide, a drug used to treat tapeworm infections, whereas the nitrothiazolyl ring shares homology with the nitroimidazole drugs metronidazole[7]. Nitazoxanide is so rapidly hydrolyzed to its active metabolite tizoxanide that it is not detectable in the blood. Most of tizoxanide (> 99%) is protein-bound and it does not significantly inhibit cytochrome P450[8]. Therefore, no significant interaction is expected when nitazoxanide is administered concurrently with agents that are metabolized or inhibited by cytochrome P450 enzymes, but it could lead to competition with other drugs that are protein-bound. Tizoxanide is then conjugated to tizoxanide glucuronide, that is inactive. One third of tizoxanide and tizoxanide glucuronide are eliminated by the urinary route and the remaining two-thirds by the biliary route[9].

Nitazoxanide displays a broad anti-infectious action, notably by inhibiting the pyruvate-ferredoxin/flavodoxin oxidoreductase-dependent electron transfer reaction, involved in the anaerobic mechanism of many microorganisms[10]. It has first been approved by the United States Food and Drug Administration for the treatment of Giardia intestinalis and Cryptosporidium parvum infections in immunocompromised patients aged 12 years or older, based on clinical trials demonstrating its efficacy in these indications[11-14]. Nitazoxanide's anti-infective activity appears to extend to other parasites[15,16], bacteria[17,18] and viruses, including enteric viruses such as rotavirus[19] or norovirus[20]. The exact mechanisms of its broad antiviral activity have yet to be specified. For instance, it has demonstrated anti-influenza activity by blocking the maturation of viral hemagglutinin at the post-translational level[21]. In the case of hepatitis C virus (HCV), activation of protein kinase R plays a key role in regulating the host's innate anti-HCV response[22]. In hepatitis B virus infection, nitazoxanide has been shown to inhibit the action of the HBx protein, which increases viral transcription and alters homologous recombination leading to tumorigenesis[23]. Finally, nitazoxanide inhibits Viral Protein 7 (VP7) and alters the formation of rotavirus viroplasms, thereby reducing its replication[24].

With regard to norovirus infection, in vitro studies have shown that tizoxanide can stimulate the innate antiviral cellular response, through the production of Interferon-Stimulated Genes, in particular Interferon Regulatory Factor 1 (IRF1). Stimulation of IRF1 was associated with a reduction in replication of Human norovirus replicons, while its knockout was responsible for a reduction in the antiviral activity of tizoxanide[25].

The efficacy of nitazoxanide in treating norovirus infections in humans has been evaluated in small randomized, placebo-controlled, double-blind trials involving immunocompetent children and adults, where it significantly reduced symptom duration[26]. In immunocompromised patients, its use for chronic norovirus diarrhea has been reported and appears promising[27,28], including in solid organ transplant recipients[29,30]. However, the drug is not yet approved for this indication.

In France, nitazoxanide is available only through compassionate use authorization, with no summary of product characteristics (SmPC). Consequently, data on the drug’s safety and tolerability remain limited.

We present the case of a 79-year-old immunocompromised kidney transplant patient who developed toxic agranulocytosis following the introduction of nitazoxanide for the treatment of chronic diarrhea caused by norovirus. To our knowledge, this is the first reported case of nitazoxanide-induced toxic agranulocytosis.

CASE PRESENTATION

Chief complaints

The patient complained of chronic diarrhea.

History of present illness

One hundred days after kidney transplantation, the patient consulted a nephrology specialist due to chronic diarrhea complicated by moderate deterioration in graft function.

History of past illness

A 79-year-old male patient presented with a history of end-stage kidney failure secondary to left partial nephrectomy (performed for clear cell renal cell carcinoma) and nephroangiosclerosis. In February 2024, the patient underwent a renal transplant from a brain-dead donor. Induction therapy consisted of Basiliximab (Simulect^®), administered at a dose of 20 mg on postoperative days 1 and 4. Maintenance immunosuppressive therapy included Tacrolimus (Prograf^®) at a dose of 0.5 mg twice daily (target concentration range: 5–8 µg/L), Mycophenolate mofetil (Cellcept^®) at 500 mg twice daily, then decreased to 250 mg twice daily, and Prednisone at 5 mg daily. Serologies for cytomegalovirus (CMV), Epstein-Barr virus (EBV), and toxoplasmosis were positive at the time of transplantation.

Personal and family history

The patient’s medical history was notable for atrial fibrillation, severe hypertension, prostatic adenoma, bladder papillary carcinoma treated with intravesical Bacillus Calmette–Guérin therapy, and superficial spreading melanoma excised 6 years ago. The prescription at entry is listed in Table 1.

Table 1 Medicines prescription when patient was admitted.

Drug	Current dosing	Previous dosing
Tacrolimus	0.5 mg morning and evening
Mycophenolate Mofetil	250 mg morning and evening	Decreased from 500 mg to 250 mg (D-12 before AD)
Cotrimoxazole	400/80 mg per day (D)
Folic acid	5 mg twice a day
Apixaban	2.5 mg morning and evening
Rilmenidine	10 mg per day	Decreased from 20 mg to 10 mg (D-12 before AD)
Nebivolol	1.25 mg per day
Furosemide	40 mg per day
Pravastatin	40 mg per day
Calcium + Cholecalciferol	500 + 400 UI twice a day
Sodium bicarbonate	1 gr per day
Darbepoetin alfa	80 micro gram once a week
Urapidil	30 mg per day	Stopped on D-12 before AD
Prednisone	5 mg a day	Stopped on D-12 before AD
Pantoprazole	20 mg a day	Stopped on D-12 before AD
Nitazoxanide	500 mg morning and evening	Added on D-18 before AD and stopped on D-4 before AD (total treatment time achieved)

AD: Admission date.

Physical examination

Treatment with nitazoxanide (500 mg twice daily) was initiated for a 14-day course, ending 4 days before admission. At treatment initiation, the absolute neutrophil count (ANC) was 2.93 G/L. Serial monitoring revealed a progressive decline in ANC: 1.8 G/L on day 3 of treatment initiation, and 1.7 G/L on Day 6, with dysgranulopoiesis observed on the blood smear. During a follow-up biology on D+3 following completion of treatment, ANC had decreased to 0.09 G/L, prompting the patient’s hospitalization the following day (Figure 1).

Figure 1 Evolution of the absolute neutrophil count (G/L) throughout time. ANC: Absolute neutrophil count.

On admission, the patient reported a 6 kg weight loss since the onset of diarrhea and exhibited signs of volume depletion, including orthostatic hypotension. Diarrhea had resolved before admission and did not recur during hospitalization. Clinical examination revealed no signs of infection, symptomatic anemia, or bleeding. Point-of-care ultrasound showed no evidence of urinary obstruction.

Laboratory findings on admission included a leukocyte count of 0.8 G/L, with ANC undetectable. Tacrolimus trough level was slightly above target (9.2 µg/L), while it was on target two weeks before, during nitazoxanide treatment (6.4 µg/L). A myelogram performed on D+7 after nitazoxanide discontinuation revealed blocked granulocyte maturation at the promyelocytic stage, with no involvement of other hematopoietic lineages, consistent with toxic agranulocytosis. Other hematological lineages were present without any observable abnormalities. Bone marrow samples tested negative for EBV, CMV, and human herpesvirus 6 (HHV-6).

Laboratory examinations

With serum creatinine levels increasing to 2.03 mg/dL (180 μmol/L) from a baseline of 1.81 mg/dL (160 μmol/L). Stool analysis revealed a positive norovirus polymerase chain reaction (PCR), with no detection of other viruses, bacteria, or parasites.

Imaging examinations

It was not necessary.

FINAL DIAGNOSIS

The regional pharmacovigilance center concluded that nitazoxanide was responsible for the agranulocytosis based on chronology and the absence of other drug introductions.

TREATMENT

Management involved hospitalization in a nephrology unit with protective isolation. The patient received two doses of lenograstim (34 MUI). Mycophenolate mofetil and cotrimoxazole were temporarily discontinued, and prednisone was reintroduced to prevent kidney transplant rejection. At discharge, mycophenolate mofetil was resumed at a reduced dose (250 mg twice daily), allowing prednisone discontinuation.

OUTCOME AND FOLLOW-UP

Hematological recovery was rapid: ANC increased to 0.7 G/L on D+7, 2.4 G/L on D+8, and 6.2 G/L on D+10 after nitozoxanide discontinuation. The evolution of ANC over time is shown in Figure 1. The patient remained asymptomatic throughout the episode, with no signs of infection or involvement of other hematological lineages

DISCUSSION

This report describes a case of agranulocytosis in a kidney transplant recipient following the introduction of nitazoxanide. This adverse effect appears to be exceptional, as evidenced by the limited data available in global pharmacovigilance databases. Only three cases of leukoneutropenia associated with nitazoxanide have been identified in the literature, including resources such as DrugDex, Martindale, the World Health Organization global pharmacovigilance database (VigiLyze), PubMed, and Google Scholar: A French HIV-infected patient treated concurrently with cotrimoxazole for Pneumocystis pneumonia, in which cotrimoxazole was deemed the most likely cause. (VigiLyze – 2008 - Pitié-Salpêtrière University Hospital, Paris, France). A patient in England with acute lymphoblastic leukemia receiving tisagenlecleucel, with Nitazoxanide’s role not excluded (VigiLyze - 2022). A United States case of leukopenia without further details (VigiLyze - 2022). To our knowledge, this is the first documented case of nitazoxanide -induced toxic agranulocytosis in the literature.

The main strength of this observation lies in the straightforward chronology: Nitazoxanide was the only new drug introduced during the weeks preceding the onset of agranulocytosis. However, the patient was concurrently receiving other medications known for their potential bone marrow toxicity, including cotrimoxazole, mycophenolate mofetil, and pantoprazole. These medications had been administered consistently since the transplantation, 4 months before onset of agranulocytosis, with no changes in pantoprazole or cotrimoxazole dosing, and folic acid supplementation was provided alongside cotrimoxazole. The dose of mycophenolate mofetil had recently been reduced, and its reintroduction at discharge did not result in agranulocytosis. Nitazoxanide pharmacokinetics data suggest a low potential for interactions. Hence, no drug interaction was found between nitazoxanide and the other treatments taken by the patient on the same time period. Among them, the following treatments have a high plasma protein binding affinity: Tacrolimus, mycophenolate mofetil, nebivolol, furosemide, and pantoprazole. However, no interaction has been reported in the literature. Given the timeline, the involvement of these drugs in causing agranulocytosis was considered negligible.

Other differential diagnoses, such as infectious causes of agranulocytosis were also considered. Viral infections, particularly those caused by EBV, CMV, and HHV-6, are well-known causes of cytopenia. However, PCR testing of blood and bone marrow samples for these viruses yielded negative results.

The mechanism by which nitazoxanide could lead to agranulocytosis is not yet known. This case shows evidence that nitazoxanide-induced agranulocytosis is linked to a direct medullary toxicity, as shown by the specific pattern on the bone marrow findings, rather than by an immune-mediated mechanism. The thiazolide class is chemically close to the nitroimidazole class, whose myelotoxic potential is well known. For example, leukopenia lower than 1.5 G/L is found in 1%-2% of patients treated with metronidazole[31], and cases of agranulocytosis have been described, reporting a direct marrow toxicity of metronidazole[32-34]. Furthermore, the administration of misonidazole, another molecule in the nitroimidazole class, has demonstrated a direct myelotoxic effect by reducing the number of granulocyte progenitor cells in the marrow[35].

It is also important to emphasize that the exact pharmacokinetics of nitazoxanide in cases of impaired renal clearance are not known. Given that one third of tizoxanide’s elimination is via urinary route, it is possible that accumulation of nitazoxanide’s metabolites could increase its toxicity, notably on the bone marrow. Dosage adjustment could therefore be beneficial in these patients but needs to be studied.

CONCLUSION

Nitazoxanide appears capable of inducing agranulocytosis, highlighting the importance of closely monitoring the absolute neutrophil count following its introduction. This agranulocytosis is likely of toxic origin rather than immuno-allergic, suggesting that reintroduction of nitazoxanide may be feasible with careful monitoring of neutrophil levels.