Critical diaphragm failure in sudden infant death syndrome 117 (31). We do not believe this contention is well sup- ported by the existing evidence. However, even those who disagree about the relative fatigue risk of the infant diaphragm agreed that it can and does fatigue under certain conditions. Infection-induced acute diaphragm weakness The central argument of the SIDS–CDF hypothesis is that even minor infections can cause a rapid and signiﬁcant reduction in diaphragm strength. Respira- tory muscle performance can decline for two reasons: due to a reduction in total muscle mass or due to a decline in muscle force generation capacity (32). The loss of muscle mass is an incremental process and is usually associated with chronic diseases such as cancer. The reduction of force generation capacity is associ- ated with acute conditions such as sepsis where muscle strength can decline signiﬁcantly within hours. We propose that an acute decline in muscle force- generating capacity is primarily responsible for CDF in SIDS cases. A large body of evidence strongly suggests that various types of infections, both viral and bacterial, can cause a signiﬁcant and acute reduc- tion in diaphragm force-generating capacity. Impor- tantly, even minor infections can signiﬁcantly reduce diaphragm strength without affecting muscle mass or histology. Acute infections were shown to reduce signiﬁcantly skeletal muscle strength in 1977 (33). Since then, numerous human and animal studies have shown that infections can induce severe diaphragm and secondary respiratory muscle weakness (34,35), whereas the cardiac muscle does not appear to be similarly vulnerable (36). Standardized endotoxins are often used to study diaphragm force reduction (37–39), but a broad range of pathogens, both viral and bacterial, has a similar effect. Human studies and animal models have shown that signiﬁcant diaphragm weakness can be induced by endotoxin injection (40), bronchopulmonary infection (41), septic peritonitis (42), parasitic infection (43), and pathogens such as Escherichia coli (44), group B Streptococcus (45), Streptococcus pneumoniae (S) (46), Pseudomonas aeru- ginosa (41), Bordetella pertussis (47), Phlebovirus (48), as well as factors associated with upper respiratory tract infection (49). A case study of an infant with vulnerable respiratory muscles illustrates the point. The patient exhibited diaphragm muscle dystrophy as the sole anomaly and suffered from episodes of severe respiratory distress that required mechanical ventila- tion to sustain life (50). Interestingly, these episodes occurred only during Staphylococcus aureus or Haemo- philus inﬂuenzae infections. The evidence cited above strongly suggests that various pathogens, both viral and bacterial in origin, can precipitate a signiﬁcant reduction in the ventilatory capacity of the diaphragm. It is well known that systemic infection can lead to severe loss of diaphragm strength and respiratory fail- ure (51). However, also less severe infections can cause a signiﬁcant reduction in the force-generating capacity of the diaphragm. Animal studies have shown that non-lethal sepsis induced by either Streptococcus pneu- moniae or E. coli with no change in blood pressure, serum electrolytes, or acid status caused a signiﬁcant impairment of diaphragm function (52). In human adults, Mier-Jedrzejowicz and co-workers observed already in 1988 that pulmonary function can deterio- rate signiﬁcantly (P < 0.05) after even apparently mild respiratory infections (53). In patients with vulnerable respiratory systems, routine infections have been shown to result in shortness of breath, reduction in vital capacity, and acute hypercapnia (49). Supinski and colleagues recently concluded that in vulnerable populations, ‘increasing evidence indicates that even minor infections can produce profound reductions in diaphragmatic force-generating capacity’ (54). A large body of experimental evidence supports this observa- tion (34,41,43,55–58). It is important to note that the degree of diaphragmatic force reduction is determined not only by the intensity of the infectious assault but also by the immune and the developmental status of the host (41,45). Fundamentally, terms such as ‘lethal’ or ‘minor’ used to characterize infections are always relative. Infections can reduce the force-generating capacity of the diaphragm by 50% in as little as 24 hours (54), and lead to severe respiratory muscle dysfunction and respi- ratory failure (45). In a study on human adults with routine upper respiratory tract infection, diaphragm strength fell signiﬁcantly (P < 0.01), with the largest decline occurring between days 3 and 7 of clinical illness (53). Full recovery of respiratory pressure took place by day 14. Numerous other studies show that a signiﬁcant reduction in diaphragm strength can occur within 1 to 48 h of infection indicating that a signiﬁcant decline in the performance of the main respiratory muscle can occur very rapidly (34,41,42,49,51,59). However, infection-induced muscle force reduction is an acute but temporary event, and the diaphragm can recover its normal function relatively quickly. This may explain why near-SIDS cases do not manifest diaphragmatic weakness (60). Animal models using either Streptococcus pneumo- niae or E. coli endotoxin show that non-lethal sepsis impairs diaphragm function without affecting muscle mass or histology (46,61). Supinski and Callahan have observed that ‘24 h after administration of endo- toxin, diaphragm speciﬁc force had fallen by 50% without any reduction in diaphragm muscle mass