Pandemic H1N1 influenza A infection and (atypical) HUS—more than just another trigger?

Abstract

Atypical hemolytic uremic syndrome (aHUS) is caused by mutations resulting in an exceedingly active alternative complement pathway. While today more than half a dozen genes are involved in aHUS pathology, only about 50% of carriers precipitate the disease. The reason for this phenomenon remains unclear, and triggering events like intercurrent infections have been postulated. In this context, reports on the development of (a)HUS in patients concomitantly diagnosed with pandemic H1N1 influenza A (pH1N1) infection are of great interest. They establish-for the first time in the literature-the link between aHUS and pH1N1 infection. While illnesses associated with pH1N1 infections during the recent pandemics were generally mild, secondary bacterial infections (e.g. Streptococcus pneumoniae) are known in patients with influenza A infections to not only aggravate the disease course, but also serve as a possible HUS trigger. Assuming pH1N1 was the cause of HUS in the cases reported here, it remains an interesting but unanswered hypothesis whether an underlying complement defect served as a susceptibility factor, at least in a subgroup of patients. In the future, pH1N1, but also pH1N1-associated, bacterial infections will have to be considered in (a)HUS patients, and further studies will be required to examine the role of the complement system in this condition.

Atypical Hemolytic Uremic Syndrome

“…In common medical language, the names typical or post-diarrheal (D+) HUS describe the most frequent form of HUS in children, due to Shigatoxin (Stx) producing Escherichia coli (STEC), mostly E coli 0157:H7. By opposition, the name atypical HUS (aHUS) has been historically used to describe any HUS not due to STEC, thus including: i) "Secondary" aHUS, due to a variety of causes, including infectious agents different from STEC, mostly Streptococcus pneumoniae (S pneumoniae) (via neuraminidase of S pneumoniae and T antigen exposure), human immunodeficiency virus and H1N1 influenza A, malignancy, cancer chemotherapy and ionizing radiation, bone marrow or solid organ transplantation, calcineurin inhibitors, sirolimus or anti vascular endothelial growth factor (VEGF) agents, pregnancy, HELLP (Hemolytic anemia, elevated Liver enzymes, and Low Platelets) syndrome, malignant hypertension, glomerulopathies, systemic diseases (systemic lupus erythematous and antiphospholipid antibody syndrome, sclerodermia) or, in children, methyl malonic aciduria with homocystinuria, cblC type, a rare hereditary defect of cobalamine metabolism [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. Of note, it is now acknowledged that using the aHUS terminology rather than an etiological-based denomination (e.g.…”

“…Interestingly, diarrhea preceded aHUS in 23% and 28% of patients in the French pediatric [17] and the Italian adult and pediatric [18] cohorts respectively, showing that the classification of HUS as (D+) or (D-) may be misleading and that post-diarrheal onset does not eliminate the diagnosis of aHUS. Other triggers such as varicella [32], H1N1 influenza [6,[33][34][35] and, interestingly, STEC-diarrhea [17,18,36,37] have been reported in patients who were investigated for aHUS because of a fulminant course, a familial incidence of the disease or the subsequent occurrence of relapses. Pregnancy is a frequent triggering event in women [18,38,39]: 20% of women with aHUS experience the disease, mostly the inaugural episode, at pregnancy, 80% of them during the post-partum period [39].…”

Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations

“…It is assumed that the virus directly affects the endothelium, thus causing TMA [137] . Another infection that has recently been recognized as a possible cause of aHUS is H1N1 influenza [138] . H1N1 could cause HUS, either favoring bacterial pathogens such as Streptococcus pneumoniae or acting as a trigger in subjects with complement abnormalities.…”

HUS and atypical HUS

“…The most frequently reported diseases that lead to clinically evident secondary HUS include infections, especially those caused by Streptococcus pneumoniae, 23 and the influenza virus. 24 These infections are considered as causes of HUS not just triggers for the disease, although the distinction between cause and trigger is not evident. In addition to infections, secondary HUS may be associated with transplantation (solid organ or bone marrow), [25][26][27][28] autoimmune disease, 29,30 cancer, 31,32 pregnancy, 33 and the use of certain cytotoxic drugs.…”