In the case we are reporting, the time between the injection of MTX and the appearance of the first signs was 2 days. This delay is comparable to that of the cases reported by Lodha et al. in India and by Shao et al. in Taiwan, which were respectively 2 days and 3 days [3, 4]. This period is shorter than in the cases reported by Toujani et al. in Tunisia and that of Soysal in Turkey, which were both 6 days [5, 6]. Note that this delay is longer than that reported by Gupta et al. in India for which it was a few hours after injection of MTX [7]. We administered a 75 mg dose of MTX. This dose of MTX is similar to that given in most patients with similar cases [5,6,7]. Note that Shao et al. reported severe reactions in a patient who received 50 mg of MTX [4]. Thus, monitoring of a patient treated with MTX should be systematic even when it is used at low doses, and continue for at least 1 week after its administration. This monitoring should take into account both the efficacy and the tolerance of the treatment.
The patient we are reporting presented with nausea and vomiting as in the cases reported by Shao et al. and by Gupta et al. [4, 7]. The patient presented with fever, as with the majority of cases reported in the literature [3, 4, 6,7,8]. The patient presented with generalized phlyctenular maculopapular rashes associated with purpuric lesions and cutaneous jaundice. These skin lesions are the same as those described in the case reported by Gupta et al. in India [7]. Skin lesions appear to be polymorphic and vary according to the cases reported. In the case reported by Lodha et al., the patient presented with plate and ulcerated generalized lesions, friable, and bleeding on contact [3]. In the case reported by Soysal et al., the patient presented macular skin rashes localized only in the thorax, neck, and scalp [5]. In the case reported by Toujani et al., the patient presented with generalized erythema with no healthy skin interval associated with ecchymotic patches on the face and limbs [6]. The patient presented with erosion of the oral and pharyngeal mucosa. These mucosal lesions have also been described in the cases reported by Toujani et al. in Tunisia and by Lodha et al. in India [3, 6]. These mucosal lesions appear to be of varying degrees, ranging from erythema of the oral mucosa to bleeding ulcers of the digestive tract [5, 7].
The patient was anemic on admission as was the case for most of the cases reported in the literature [3, 5, 8]. As in our case, pancytopenia seems constant during severe reactions to MTX [3, 4, 6,7,8]. Our patient presented with febrile neutropenia as in the cases reported by Shao et al. in Taiwan and that of Lodha et al. in India [3, 4]. Note that febrile neutropenia is not constant and was absent for the cases reported by Gupta et al., Soysal et al., and Jebasingh et al. [5, 7, 8]. In our case, there was no renal failure as in the cases reported by Shao et al. in Taiwan and by Jebasingh et al. in India [4, 8]. Our case differs from those reported by other authors in which treatment with low-dose MTX was complicated by renal failure [3, 6, 7]. The patient presented with hepatic cytolysis as in the cases reported by Toujani et al. in Tunisia and by Gupta et al. in India [6, 7]. Due to the quality of the chest x-ray, it was not possible to formally confirm the presence of infiltrative lung disease, which was present in the cases reported by Toujani et al. as well as Gupta et al. [6, 7]. Serum methotrexate level was not measured for our patient as was the case for the majority of reported cases [3, 4, 7]. This is because serum methotrexate level is not available in Madagascar and requires the sending of blood samples abroad. This is generally high for cases for which it could be measured [5, 6]. We remind that the mechanism of toxicity of MTX is not fully understood. Indeed, pancytopenia, digestive intolerance, and stomatitis are explained by the deficiency in folinic acid. The mechanisms are more complex for renal failure, hepatic cytolysis, and pulmonary fibrosis [1].
Regarding management, the patient we are reporting did not benefit from granulocyte growth factors unlike the majority of reported cases [3, 4, 7]. Our case did not benefit from broad-spectrum antibiotics recommended in febrile neutropenia unlike cases reported in the literature [3,4,5,6, 8]. Our patient did not receive folinic acid. Folinic acid, which is the “antidote to MTX,” was used routinely in other reported cases even in the absence of serum methotrexate level [3,4,5,6,7,8]. Our patient did not benefit from a platelet pellet unlike the cases reported by Shao et al. and by Soysal et al. [4, 5]. Plasmapheresis, which is also an option for rapidly lowering MTX levels, was not used in the patient [5]. Our therapeutic management is explained, on the one hand, by the fact that the platelet pellet and plasmapheresis are not available in Madagascar. On the other hand, the very rapid deterioration of the patient’s condition did not give her family time to buy the granulocyte growth factors and folinic acid, the costs of which remain their responsibility.
The patient's hospital stay (2 days) is short compared with that reported in the literature, which was respectively 4, 14, 14, 18, and 21 days for Toujani et al., Jebasingh et al., Lodha et al., Soysal et al., and Shao et al. [3,4,5,6, 8]. As in the case reported by Tounaji et al. in Tunisia, the patient that we report died of multiple organ failure [6]. This contrasts with the evolution of Asian cases, which was generally favorable with normalization of the blood count and disappearance of skin and mucous lesions [3,4,5, 7]. Before initiating treatment with MTX, the practitioner must first ensure that there are no absolute and relative contraindications to this treatment [1]. In the event of severe reactions, the management should be multidisciplinary and as much as possible within an intensive care unit.
The case we are reporting differs from the data in the literature by the absence of serum methotrexate level, the absence of the use of granulocytic growth factors, antibiotics for febrile neutropenia, folinic acid, and platelet pellet. It is also distinguished by a very short hospital stay, which resulted in a fatal outcome. In this case, the main problems leading to death of the patient were the lack of broad-spectrum antibiotics for the febrile neutropenia and the lack of folinic acid. The dose and route of MTX were correctly chosen. Neutropenia due to low-dose MTX is rare and can occur after varying times, making it difficult to anticipate. The takeaway main points are that the clinician should always advise the patient of the possibility of these serious side effects, even though they are rare with low-dose MTX. Monitoring of the patient treated with MTX should be systematic even when used at low doses and should be continued for at least 1 week after administration. In the event of severe reactions, the management should be multidisciplinary and as much as possible within an intensive care unit. Emergency supplies of broad-spectrum antibiotics and folinic acid could be lifesaving in the event of similar events. A prospective study on patients treated with MTX would allow us to know the real frequency of side effects and their severity.
