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Vol. 27. Issue 3.
Pages 269-272 (May - June 2021)
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Vol. 27. Issue 3.
Pages 269-272 (May - June 2021)
Letter to the Editor
DOI: 10.1016/j.pulmoe.2020.04.006
Open Access
Rifampicin-induced disseminated intravascular coagulation: An antibody-mediated side effect
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G. Sousaa,
Corresponding author
gsousa1@campus.ul.pt

Corresponding author.
, A. Carreirob, P. Duartec
a Intensive Care Medicine Department, Hospital do Divino Espírito Santo, Ponta Delgada, Portugal
b Pulmonology Department, Hospital do Divino Espírito Santo, Ponta Delgada, Portugal
c Internal Medicine Department, Hospital do Divino Espírito Santo, Ponta Delgada, Portugal
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Tables (2)
Table 1. Laboratory data. Evolution of two DIC episodes.
Table 2. Cases of RFM-induced DIC previously described in the literature.
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Dear Editor,

Rifampicin (RFM) remains an effective treatment of pulmonary tuberculosis. Gastrointestinal adverse effects and liver toxicity are common. However, more serious reactions such as haemolytic anaemia, acute renal failure, and disseminated intravascular coagulation (DIC) have only been rarely documented. DIC secondary to RFM is a consequence of a rare immunoallergic reaction caused by the intermittent administration of RFM. It is even more uncommon in the absence of neoplastic disease, severe infection or previous exposure to RFM. Clinical features of that reaction include fever, hypotension, abdominal pain, and vomiting within hours of ingestion. Future administration of RFM is life-threatening and is contraindicated.

The aim of this report is to describe a case of RFM-induced DIC and to perform a review of the previous reports of this uncommon finding. The Pubmed® database was searched for articles in English that were published between January 1990 and January 2020. We combined search terms RFM and DIC. We also manually searched the reference lists of the eligible studies.

The authors present the case of a 68-year-old man with a history of pulmonary tuberculosis diagnosed in 2007 which was reactivated in 2018. He started the treatment with RFM, isoniazid (IZD), pyrazinamide and ethambutol. Two months later, given the clinical improvement and negative acid-fast bacilli smear, he continued the treatment with RFM and IZD. However, due to gastrointestinal symptoms (nausea and abdominal pain), the patient was following treatment intermittently (on his own initiative).

After one week of interruption, the patient returned to the treatment with RFM and IZD. One hour after, he was admitted to the Emergency Department because of a sudden onset of dyspnoea, nausea, and abdominal pain. He was in respiratory distress, febrile, hypotensive, and tachycardic. The laboratory analysis revealed low platelets (28,000/μL) and d-dimer elevation (43,290ng/ml) – Table 1.

Table 1.

Laboratory data. Evolution of two DIC episodes.

VariableReference range, adults, this hospitala1st episode of DIC10th day (ICU)2nd episode of DIC
1h6h25h
Haemoglobin (g/dL)  14.0–18.0  RFMSudden onset dyspnoea, nausea, and abdominal pain13.7  Haemorrhagic dyscrasia11.6  Recovery8.5  RFMNon-specific malaise, nausea, and abdominal painHaemorrhagic dyscrasia5.2  Death
Platelets (/μL)  150–400,000  28,000  38,000  573,000  21,000 
PT (s)  9.4–13.4  11.9  37.8  15.3  26.8 
APTT (s)  24.0–37.0  28.8  8.1  30.2  79.9 
Fibrinogen (mg/mL)  200–400  –  Very low (not measurable)  981  157 
D-dimers (ng/mL)  0–250  43,290  1403  65,236 
a

Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used in Hospital do Divino Espírito Santo, Ponta Delgada; are for adults who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients.

Six hours after the RFM intake, the patient presented haemorrhagic dyscrasia with hemoptoic sputum, bleeding through the vascular accesses, haematuria, and haematochezia. The analytical study was compatible with DIC, showing low platelets (38,000/μL) and prolonged prothrombin time (PT) 37.8s; a prolonged activated partial thromboplastin time (APTT) 81.1s, and a very low fibrinogen level (not measurable) – Table 1. Chest angio-CT scan excluded pulmonary embolism and it revealed a ground-glass opacity infiltrate in the right lower lobe suggestive of inflammatory/infectious process.

DIC secondary to probable septic context, due to community-acquired pneumonia, was assumed. Samples were collected for cultural exams and ceftriaxone was initiated. The patient was admitted to the Intensive Care Unit (ICU).

During his stay in ICU, the patient presented good clinical and analytical recovery. On the 10th day of hospitalization, given the stability, the patient returned RFM. The analytical study (prior to RFM intake) showed no relevant changes – Table 1. Two hours after taking RFM, the patient started having nausea and abdominal pain. Five hours after RFM, a new episode of haemorrhagic dyscrasia was seen with hematemesis, bleeding through the vascular accesses and macroscopic haematuria. Hypotension refractory to fluids and vasopressor support was documented. Six hours after the RFM intake the patient presented cardio-respiratory arrest and death. Analytical study showed acute decrease in haemoglobin level (5.2g/dL) and DIC criteria with low platelets (21,000/μL), coagulopathy (PT 26.8s; APTT 79.9s; low fibrinogen 157mg/ml) and d-dimers elevation (65236ng/ml) – Table 1. Post mortem study revealed anti-RFM positive antibodies (IgM and IgG) in the patient's serum.

The adverse effects of RFM, include IgE-mediated allergic reactions like rashes, mild gastrointestinal disorders, hepatotoxicity, and drug interactions.1 In contrast, intermittent intake of RFM can produce more serious adverse effects induced by immunoallergic reactions mediated by IgG and IgM antibodies against erythrocytes, platelets and other target cells expressing blood antigen I, including renal tubular epithelial cells.2 Clinical manifestations of these reactions begin within hours after the ingestion of RFM and include vomiting, abdominal pain, fever, and hypotension. Diagnostic investigations generally reveal the presence of renal dysfunction, intravascular haemolysis, and DIC. The review of the existing literature identified only 13 previously reported cases of RFM-induced DIC2–4; this is the 14th case described (Table 2).

Table 2.

Cases of RFM-induced DIC previously described in the literature.

Author  Study design  Case no. Author  Age (years)/gender  Diagnosis  Dosage  Prior exposure  Time to development of DIC  Clinical features  Outcome 
Havey et al.2Case report and review1. Brasil et al.2  NA/M  600mg/month  Yes  3 doses  NA  Death 
2. Denis et al.2  48/F  600mg/day  NA  5 months  Fever, jaundice, vomiting, diarrhoea  Recovery 
3. Fujita et al.2  43/M  450mg/day  NA  7 days  Bleeding  Recovery 
4. Ip at al.2,5  29/F  600mg, three times a week  Yes  6 months  Fever, hypotension, vomiting, oliguria, pruritis  Recovery 
5. Luzzati et al.2,6  35/M  600mg/day  Yes  1 dose  Fever, rash, hypotension, abdominal pain, vomiting, myalgias  Recovery 
6. Namisato and Ogawa2  64/M  600mg/month  Yes  3 doses  Fever, hypotension, facial oedema, vomiting, abdominal pain  Recovery 
7. Nowicka et al.2  53/F  450mg; dosing schedule unclear  Yes  3 doses  Lumbar and abdominal pain, anuria  Death 
8. Souza et al.2  46/F  600mg/month  Yes  3 doses  Fever, haematuria  Death 
9. Havey et al.2  66/F  600mg/month  Yes  6 doses  Fever, hypotension, vomiting, abdominal pain, oliguria  Recovery 
Sadanshiv et al.3Case report and review10. Costiniuk et al.3  20/F  600mg/day  Yes  3 weeks  Renal failure, non-bloody diarrhoea, hypotension, vomiting, decreased urine output, haemolysis  Recovery 
11. Soltani et al.3  71/F  600mg/day  No  7 days  Renal failure, haemolysis, abdominal pain, vomiting, jaundice, decreased urine output  Recovery 
12. Sadanshiv et al.3  50/F  600mg, single dose  Yes  1 day  Renal failure, haemolysis, dark-coloured urine, jaundice, fever, vomiting, decreased urine output  Recovery 
Chen et al.4  Case report  13. Chen et al.4  22/M  450mg/day  Yes  7 days  Epistaxis, haematochezia, haematuria, purpura, jaundice  Recovery 
14. Present case68/M  600mg/day  Yes  3 months  Fever, hypotension, abdominal pain, haemolysis, hemoptoic sputum, bleeding through the vascular accesses, haematuria, haematochezia  Death 

T – tuberculosis; B – brucellosis; L – leprosy; NA – not available.

In the case reported, as in 3 cases before, the fact that sepsis is a common source of DIC made diagnosis difficult.2 This led to the re-exposure to RFM with a new episode of DIC and a fatal outcome. 3 other fatal cases have already been documented.2 The prior treatment with RFM, the temporal association between the two episodes of DIC and the RFM intake, as well as the absence of new episodes after its interruption, pointed to the causal role of the drug in the case described. The suspicion was confirmed post mortem by the detection of anti-RFM IgG and IgM antibodies in the patient's serum. However, DIC due to RFM is a clinical diagnosis and it has been confirmed by antibodies in only two cases before.5,6 The present case is intended to draw attention to a rare side effect of a commonly used drug.

Acknowledgments

Doctor Cristina Fraga, Director of Haematology Department, Hospital do Divino Espírito Santo, Ponta Delgada, E.P.E.

References
[1]
E.J. Forget, D. Menzies.
Adverse reactions to first-line antituberculosis drugs.
Expert Opin Drug Saf, 5 (2006), pp. 231-249
[2]
T.C. Havey, C. Cserti-Gazdewich, M. Sholzberg, J.S. Keystone, W.L. Gold.
Recurrent disseminated intravascular coagulation caused by intermittent dosing of rifampicin.
Am J Trop Med Hyg, 86 (2012), pp. 264-267
[3]
M. Sadanshiv, A.A. George, A.K. Mishra, C.K. Ajay Kuriakose.
Rifampicin-induced immune allergic reaction.
Trop Doctor, 48 (2017), pp. 156-159
[4]
G. Chen, J. He.
Rifampicin-induced disseminated intravascular coagulation in pulmonary tuberculosis treatment.
Medicine, 96 (2017), pp. 6135
[5]
M. Ip, K. Cheng, W. Cheung.
Disseminated intravascular coagulopathy associated with rifampicin.
Tubercle, 72 (1991), pp. 291-293
[6]
R. Luzzati, D. Giacomazzi, F. Franchi, M. Barcobello, S. Vento.
Life-threatening. Multiple hypersensitivity reactions induced by rifampicin in one patient with pulmonary tuberculosis.
Southern Med J, 100 (2007), pp. 854-856
Copyright © 2020. Sociedade Portuguesa de Pneumologia
Pulmonology

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