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high dose ( hd ) mtx ( 0.5 - 12 g / m ) has antiproliferative activity and is used in treatment of cancer while low dose ( ld ) mtx ( 10 - 40 mg/ m ) has anti - inflammatory and immunosuppressive properties .
reports of acute mtx toxicity presenting as multiorgan failure and acute pneumonitis are rare ( mtx - p ) .
a 48-year - old , male with a 2-year history of plaque psoriasis affecting limbs and trunk was advised 5 mg of oral mtx thrice weekly . however , accidentally he ingested three tablets daily ( 5 mg each ) for 4 days i.e. , total dose of 60 mg . a week later , he presented to the emergency department with nausea , vomiting and painful skin erosions over the trunk and intertriginous areas .
on examination was icteric , tachycardic ( hr = 110/ min ) , arterial blood pressure bp = 136/54 mmhg , and tachypnoeic ( rr = 38/min ) .
he was conscious and oriented . at admission , laboratory investigations revealed pancytopenia , other investigation on day 1 are listed in table 1 .
bilateral diffuse infiltrates seen on chest x - ray [ figure 1 ] , were believed to be due to pneumonia as his echocardiography and lower limb doppler were all within normal limits .
clinical and laboratory parameters day 1 chest x - ray suggestive of interstitial edema arterial blood gas analysis revealed hypoxemia with primary respiratory alkalosis .
intravenous folinic acid at dose of 15 mg was given 6 hourly ( 1 mg / kg ) .
subcutaneous granulocyte colony - stimulating factor ( g - csf ) 350 g was also given .
as his urinary ph was 5.9 , sodium bicarbonate 20 meq / hr was added along with 1 l bolus followed by 100 ml / hr of normal saline to aid in alkalinization of urine ( target urinary ph = 7.0 ) . after collecting cultures ,
patient was started on broad spectrum empiric antibiotics ( meropenem and teicoplanin ) and antifungals ( fluconazole ) in view of neutropenia . within 24 hours
the patient 's urine output improved and after 48 hours his platelet and leukocyte count also started increasing . within 72 hours , he was extubated and was transferred to ward in another 2 days .
as there was no evidence of infection ( cultures sterile and normal procalcitonin ) antibiotics were stopped after 5 days .
acute pneumonitis with ld- mtx ( 10 - 40 mg / m ) given over short span of time ( 4 days ) has been rarely reported .
patients with pre - existing lung disease , rheumatoid arthritis , old age and on previous use of disease - modifying anti - inflammatory rheumatic drugs ( dmards ) are at heightened risk of developing mtx pneumonia .
methotrexate pneumonitis occurs most frequently within the first year of treatment and its reported incidence varies from 0.86 to 6.9% .
we reviewed literature regarding development of acute pneumonitis within 1 week of ld - mtx exposure .
only three case reports , one by ridley et al . about a middle - aged woman who developed acute pneumonitis 1 week after intake of 12.5 mg of mtx .
similarly two cases of acute pneumonitis were reported in patients with ectopic pregnancy given mtx . in first case mtx pneumonitis was linked with rheumatoid arthritis , while other two cases were due to idiosyncratic reaction .
type 1 occurs with low mtx exposure ( < 300 mg ) , with early ( < 6 months ) onset , dominated by neutrophils , has lung fibrosis , and carries high mortality .
type 2 occurs with high mtx exposure ( > 600 mg ) with late ( > 6 months ) onset , dominated by lymphocytes , has less lung fibrosis and carries low mortality .
the mechanism of mtx - p is cell - mediated hypersensitivity reaction mediated by activated t - cells .
mtx stimulates type ii alveolar cells to release cytokines which lead to inflammatory cells recruitment leading to alveolitis .
acute pulmonary toxicity however appears to be unrelated to either the dose or the duration of treatment .
one important variable appears to be the frequency of drug administration ; since patients receiving daily or even weekly doses have a higher risk of toxicity than those receiving the drug less frequently . although exact mechanism is still debatable . in our case
our patient had ( 1 ) acute onset of dyspnea , ( 2 ) fever > 38c , ( 3 ) tachypnoea > 35/min , and dry cough , ( 4 ) radiological evidence of pulmonary interstitial infiltrates ( 5 ) wbc <
1,000/cumm without eosinophilia , ( 6 ) negative blood and sputum cultures , ( 7 ) po2<60 mmhg on room air , which fulfilled seven of nine criteria for diagnosis of pneumonitis as described by searles and mckendry . similarly according to 2008 diagnostic criteria for mtx pneumonitis , our patient fulfilled five out of eight criteria . according to both these criteria our patient had definite mtx pneumonitis .
high - resolution computerized tomography ( hrct ) was contemplated but deferred since his clinical condition improved rapidly .
mtx toxicity has its impact on skin , gastrointestinal mucosa , liver , kidneys , and bone marrow .
sites with rapid cell turnover like skin and gastrointestinal mucosa are the earliest to get involved .
ninety - eight percent of the oral mtx is excreted via the renal route . at low levels
however , at extremely high tubular concentrations there is impairment of active tubular secretion which increases likelihood of toxicity .
hd - mtx exposure patients with elevated baseline creatinine of  50% , have 55% incidence of myelosupression as against only 3% with normal renal function . myelosupression occurs on day 8 - 10 and there is spontaneous recovery at three weeks .
supportive measures include leucovorin ( folinic acid ) , alkalinization of urine , intravenous hydration , g - csf and blood products .
although corticosteroids are frequently administered , there are no large trials suggesting their efficacy as yet . as steroids may increase the risk of superinfections we avoided it due to coexisting neutropenia in our case .
our case had accidentally ingested large amount ( 60 mg ) of ld - mtx , and developed immediate stomatitis , nausea and vomiting .
after 96 hours , he developed cough with respiratory distress ( acute pneumonitis ) , decreased urine output ( aki ) , and yellowish discoloration of urine , altered lft ( hepatitis ) .
as his gfr diminished , there was accumulation of mtx leading to myelosupression and pancytopenia .
mtx - p though , related mostly to chronic ld - mtx but as in our case can also occur acutely if large doses of ld - mtx are ingested .
it is a transient hypersensitivity reaction with good prognosis , if aggressive management is instituted promptly .
this case report highlights the importance of early follow - up and regular laboratory investigations of patients on methotrexate therapy .
acute methotrexate toxicity rarely presents as medical emergency in form of multiorgan failure . 
 acute pneumonitis following low - dose methotrexate is rarely reported in literature . 
 it is important to recognize this , as the drug must be discontinued immediately and rescue measures in form of folinic acid and hydration instituted promptly .