Keywords:
The pandemic influenza A (H1N1) virus has been spreading throughout the world since May 2009. A second wave and multiple mutations of the virus have also been confirmed in 2010. Several studies have described the clinical characteristics, the effect on respiratory capacity, the cost–effectiveness of protective measures and antibiotics or antivirals, and also evaluated the effectiveness of vaccination. Moreover, multiple studies have described the radiographic pattern of the H1N1 infection and especially the diffuse like pneumonitis that is observed with acute respiratory distress in young adults or the middle-aged. Other studies have extensively described the effect of H1N1 influenza A on individuals with a background of respiratory disease. Assessment of patients with cancer or coronary heart disease as comorbidities have also been included in published studies. The subgroup of patients that remain to be thoroughly investigated are the patients with diabetes mellitus. It has been reported that influenza A (H1N1) induces a ‘cytokine storm‘ that affects many systems. Diabetes mellitus is a disease where immunodeficiency silently underlies and deregulates the immune system. A retrospective study evaluating the clinical manifestations of the pandemic H1N1 in this subgroup of patients could offer valuable insight on this hypothesis revealing whether these patients are more affected than other groups.
In June 2009, the WHO announced that a novel H1N1 flu pandemic was on its way Citation[1]. Since then, several studies have presented clinical data on clinical outcomes and laboratory findings from affected patients Citation[1–3]. In addition, a mutation has been observed in the virus on the first wave, and also in the waves that followed Citation[4,5]. To make matters worse, acquired resistance to oseltamivir, the agent of choice for H1N1 infection, was also observed in both waves Citation[6]. Of further significance, there is evidence that this virus may induce a ‘cytokine storm‘ by releasing several proinflammatory mediators, most notoriously IL-6 Citation[7–9]. An indirect observation that the virus affects the respiratory system has been derived from lung function tests performed in a small cohort study Citation[2].
Most studies on H1N1 were retrospective and very few were prospective Citation[10]. In the majority of these works, comorbidities were carefully assessed. As might be anticipated, the main emphasis has been on respiratory tract diseases Citation[1,3]. Nevertheless, a large number of the patients had diabetes mellitus, a disease known to be associated with some compromise of the immune system Citation[11,12]. Thus far, the correlation between these two entities in terms of clinical outcomes has not been investigated. Indeed, patients with both diabetes mellitus and H1N1 influenza have merely been a part of a larger group labeled ‘subjects with underlying diseases‘.
In this context, there are several points to address. First, it is reasonable that H1N1 deregulates the immune system more profoundly in patients with diabetes mellitus. However, this remains to be demonstrated by careful analysis. Secondly, the next step towards defining the proper treatment for this group of patients can only be achieved through prospective studies recruiting H1N1-positive patients with diabetes mellitus. Moreover, a relevant subgroup analysis including patients from prior studies would be extremely useful in defining the potential differences in clinical outcomes and/or appropriate treatment. Thirdly, the H1N1-induced ‘cytokine storm‘ can be mitigated with the immunomodulatory and anti-inflammatory properties of macrolides and/or N-acetylcysteine Citation[13]. Accordingly, it is desirable to explore the potential of these agents in diabetic patients with H1N1 infection. Finally, we should examine the hypothesis that such patients might benefit from additional interferon during acute H1N1 infection, given the beneficial immune-modulatory actions of this agent Citation[14]. This biologic treatment modality could be applied as an antiviral or in combination with the antibiotic drug used. Based on published literature, biologic therapies using h-peg-interferon-α-2b, peg-interferon-α-2a, interferon-β-1a and interferon-β-1b in systemic diseases such as multiple sclerosis and rheumatoid arthritis has shown promising results. Since diabetes mellitus is considered a systemic disease, the immune system dysregulation from H1N1 could be further controlled Citation[15].
In conclusion, the interplay between H1N1 infection and diabetes mellitus is very interesting and may be manifold. Indeed, we have a lot to learn in this field, and relevant studies would be most welcome to increase our understanding. Meanwhile, H1N1-positive patients with diabetes should receive the same treatment and other measures as those without diabetes.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
References
- Cao B , LiXW, MaoY et al. Clinical features of the initial cases of 2009 pandemic influenza A (H1N1) virus infection in China. N. Engl. J. Med.361(26) , 2507–2517 (2009).
- Zarogoulidis P , KouliatsisG, PapanasN et al. Long-term respiratory follow-up of H1N1 infection. Virol. J.8 , 319 (2011).
- Zarogoulidis P , ConstantinidisT, SteiropoulosP, PapanasN, ZarogoulidisK, MaltezosE. Are there any differences in clinical and laboratory findings on admission between H1N1 positive and negative patients with flu-like symptoms?. BMC Res. Notes1(1) , 141 (2011).
- Maurer-Stroh S , LeeRT, EisenhaberF, CuiL, PhuahSP, LinRT. A new common mutation in the hemagglutinin of the 2009 (H1N1) influenza A virus. PLoS Curr.2 RRN1162 (2010).
- Strengell M , IkonenN, ZieglerT, JulkunenI. Minor changes in the hemagglutinin of influenza A(H1N1)2009 virus alter its antigenic properties. PLoS One6(10) , e25848 (2011).
- Hurt AC , DengYM, ErnestJ et al. Oseltamivir-resistant influenza viruses circulating during the first year of the influenza A(H1N1) 2009 pandemic in the Asia–Pacific region, March 2009 to March 2010. Euro. Surveill.16(3), pii: 19770 (2011).
- Svitek N , RuddPA, ObojesK, PilletS, von Messling V. Severe seasonal influenza in ferrets correlates with reduced interferon and increased IL-6 induction. Virology376(1) , 53–59 (2008).
- To KK , HungIF, LiIW et al. Delayed clearance of viral load and marked cytokine activation in severe cases of pandemic H1N1 2009 influenza virus infection. Clin. Infect. Dis.50(6) , 850–859 (2010).
- Lee N , ChanPK, WongCK et al. Viral clearance and inflammatory response patterns in adults hospitalized for pandemic 2009 influenza A(H1N1) virus pneumonia. Antivir. Ther.16(2) , 237–247 (2011).
- Fabbiani M , SaliM, Di Cristo V et al. Prospective evaluation of epidemiological, clinical, and microbiological features of pandemic influenza A (H1N1) virus infection in Italy. J. Med. Virol.83(12) , 2057–2065 (2011).
- Johnston SL , VirgoPF, UnsworthDJ. Type 1 diabetes mellitus masking primary antibody deficiency. J. Clin. Pathol.53(3) , 236–237 (2000).
- Hermaszewski RA , WebsterAD. Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications. Q J Med.86(1) , 31–42 (1993).
- Zarogoulidis P , PapanasN, KioumisI, ChatzakiE, MaltezosE, ZarogoulidisK. Macrolides: from in vitro anti-inflammatory and immunomodulatory properties to clinical practice in respiratory diseases. Eur. J. Clin. Pharmacol.68(5) , 479–503 (2011).
- Yan B , YeS, ChenG, KuangM, ShenN, ChenS. Dysfunctional CD4+,CD25+ regulatory T cells in untreated active systemic lupus erythematosus secondary to interferon-alpha-producing antigen-presenting cells. Arthritis Rheum.58(3) , 801–812 (2008).
- Lacana E , AmurS, MummanneniP, ZhaoH, FruehFW. The emerging role of pharmacogenomics in biologics. Clin. Pharmacol. Ther.82(4) , 466–471 (2007).