An urgent study on NSAIDs use is needed in Mexico

27 May 2009

Shimazu's comments are very important [1] in considering the high case mortality
Chairperson: Japan ratio in Mexico in the 2009A/H1N1 epidemic [2].
Rokuro Hama,

Institute ofPharmacovigilance,
Editor:According to the data reported from WHO [2], case fatality ratios in adults were
3.7 % for all adults (20-29y: 2.8 %, 30-49y: 4.0 %, >=50y: 5.6 %), while 0.6 % inchildren aged less than ten and 0.4 % in teenagers (combined: 0.5 %).

Kusuri-no-Check (aMortality ratio in those in each ten years of age from 20-59 and in those 60 years
old or more is significantly higher than each ten years of age in those less than#902
twenty years old. According to my reanalysis of the WHO's data, odds ratio (OR) ofUeshio3-2-17,
case fatality of combined adults compared with combined children and teenagers
Tennoji-ku Osaka,(0-19 yeas) is 7.63 (95% confidence interval (CI): 3.78-15.85, p=0.0000000). The
Japan 543-0002
authors say "Reasons to be determined".
drug bulletin)

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Re: An urgent
study onNSAIDs use isneeded inMexico

Several cases experiencing cardiopulmonary arrest shortly after arrival at hospital,
rapid progression to acute respiratory distress syndrome (ARDS) and renal or
multi-organ failure are reported in 24% of fatal cases [2]. Both leukocytosis andleucopenia are reported [2] and both are the fundamental diagnostic criteria ofsepsis: i.e. systemic inflammatory response syndrome (SIRS) due to infection.
Bacterial co- infections were rarely documented (only in 3 among 45 fatal cases).
Laboratory findings such as high levels of aminotransferases and creatinine
phosphokinase, skeletal muscle necrosis, renal insufficiency, hypotension andeven myocarditis often reported as clinical or autopsy findings in fatal cases in thisreport [2] are also the common findings in sepsis-multiorgan failure syndrome withor without shock induced by the systemic cytokine storm in viral infections.
Mizuguchi et al [3] reviewed acute encephalopathy as one of the most serious
complications of pediatric viral infections. Of the three major groups, the secondgroup which is characterized by a systemic cytokine storm and vasogenic brain
edema, includes Reye-like syndrome, hemorrhagic shock and encephalopathy
syndrome, and acute necrotizing encephalopathy [3]. Non-steroidal
anti-inflammatory drugs, such as diclofenac sodium and mephenamic acid, may
aggravate these syndromes [3]. Severe cases are complicated by multiple organ
failure and disseminated intravascular coagulation [3].
These clinical and epidemiological evidences are consistent with the results ofmeta-analysis of experimental studies using infected animals [4,5].The authors of WHO warned "Salicylates (such as aspirin and aspirin- containingproducts) should not be used in children and young adults because of the risk ofReye syndrome."
However use of salicylates is neither restricted in adults nor use of other NSAIDs
including ibuprofen is restricted in any age, though they warned of the use ofcorticosteroids referring the experience of SARS (severe acute respiratory
syndrome) and increased mortality in avian influenza A (H5N1) disease [6].
The authors of WHO [2] discussed about the risk factors for severe or complicateddiseases. They mentioned relatively common but unspecific risk factors such as
smoking, air pollution, high altitude (Mexico City at >2200 m). However thepossibility of harmful effects of NSAIDs is not discussed.
Washington Post [7] reported that the uninsured, about 50 percent of thepopulation, include the unemployed and those who work in the informal economy.
They also reported a doctor's comments saying "In Mexico, we are very
unaccustomed to going to the hospital. Here, if someone has a cold or anythingelse, they buy something in the pharmacy, or they leave it be,"Doesn't something in the pharmacy mean aspirin and/or NSAIDs antipyretics,and/or drugs containing these?
I strongly propose first of all, an urgent retrospective study to reveal whether
NSAIDs were used or not in severe and fatal cases before they deteriorated.
If NSAIDs are highly used before deterioration, then a case- controlled study toconfirm the relation of NSAIDs to the high fatality should be carried out.
Errata:In my previous response [1], the 2 parts should be read as follows:#1 The 12th line from the bottom of the text:
restricted to the treatment-->restricted in the treatment#2 The 7th line from the bottom of the text:
restricted to children-->restricted in children .
References
1.Shimazu T. Aspirin may be the enhancer of virulence in 1918 pandemic
http://www.bmj.com/cgi/eletters/338/may12_3/b1962#214298
2. WHO, Human infection with new influenza A (H1N1) virus: clinical observations

from Mexico and other affected countries, Weekly epidemiological record,2009,
84(21) 185-189. http://www.who.int/wer/2009/wer8421.pdf
3. Mizuguchi M, Yamanouchi H, Ichiyama T, Shiomi M. Acute encephalopathy
associated with influenza and other viral infections. Acta Neurol Scand. 2007
Apr;115(4 Suppl):45-56 http://www.ncbi.nlm.nih.gov/sites/entrez
4. Hama R, Fatal neuropsychiatric adverse reactions to oseltamivir: case series
and overview of causal relationships. The International Journal of Risk & Safety inMedicine (2008) 20: 5-36. available at :http://npojip.org/sokuho/published-paperJRS431.pdf
5.Hama R. NSAIDs may be more harmful than paracetamol: based on the best
evidence available. http://www.bmj.com/cgi/eletters/333/7557/4
6. Writing Committee of the Second World Health Organization Consultation onClinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus. Updateon avian influenza A (H5N1) virus infection in humans. New England Journal ofMedicine, 2008, 358:261・73 (available at
http://content.nejm.org/cgi/reprint/358/3/261.pdf ; accessed May 2009).
7. Washington Post. Poverty, Tendency to Self-Medicate Help Drive Up Flu Deathsin Mexico http://www.washingtonpost.com/wpdyn/content/article/2009/05/04/AR2009050403755_2.html?sid=ST2009050302126
Competing interests: None declared