Diabetes Mellitus and Infection
Some types of infection occur more frequently in patients with diabetes. This increased risk is largely attributable to an altered immune response due to chronic hyperglycaemia, but increased susceptibility to infection may also result from diabetic complications such as diabetic neuropathy and vascular insufficiency. Risk of most common infections is only modestly increased (e.g. 1.2 fold), but a number of rare but potentially fatal infections occur primarily or even almost exclusively in patients with diabetes. These include mucormycosis, emphysematous urinary tract infections, emphysematous cholecystitis, necrotizing fasciitis and malignant otitis externa. Immediate antimicrobial and/or surgical treatment is needed to prevent serious complications from these infections, including death. In general, antimicrobial treatment of infections in patients with diabetes is not different than in patients without diabetes. Glucose lowering therapy often needs to be increased to counter the loss of control associated with infection. Vaccinations against influenza and pneumococcal infections are recommended for patients with diabetes.
Incidence and contributing factors
People with diabetes are reported to experience 21% more infections than the general population. Several factors may contribute to this, for example possible ‘reporting bias’: more frequent medical visits due to diabetes may lead to better recording of infectious complications. Even so, it seems clear that the risk of many common infections increases in proportion to hyperglycemia. Special problems may also arise in relations to diabetic nephropathy, which may undermine host defences against infection, and peripheral vascular disease which may impair tissue nutrition, oxygen supply and the ability to mount an effective immune response. Peripheral neuropathy also increases the risk for diabetic foot infections.
Immune system in diabetes mellitus
Hyperglycemia may compromise the immune system. Ex-vivo experiments, in which human cells are analysed in a laboratory environment outside of the body, show that innate cellular immunity may be compromised in hyperglycemic conditions. In a hyperglycemic or acidic environment neutrophils and macrophages malfunction, and restoring normoglycemia and a normal pH reverses these abnormalities.
The adaptive cellular immune system may also be compromised, but evidence is sparse. T-cell function may be compromised, especially in hyperglycemic conditions. There is no evidence that the humoral adaptive immune system functions differently in patients with diabetes: this is illustrated by the fact that the antibody response to vaccinations seems to be as effective as in healthy controls. 
Rare and potentially serious infections that occur primarily in patients with diabetes
Rhinocerebral or systemic mucormycosis is a rare fungal infection that will be fatal if left untreated for 7-10 days. A review of English language literature reported that 36% of all patients mucormycosis have diabetes mellitus. In an Indian cohort followed between 2000-2004, a concomitant diagnosis of diabetes was found in over 70% of patients. Especially patients with uncontrolled diabetes and acidosis are at risk for mucormycosis. It is not uncommon that diabetic ketoacidosis preceded the diagnosis of mucormycosis. Presenting symptoms of rhinocerebral mucormycosis are a sharp pain and redness in the periorbital area, swelling of an eyelid. If the disease is left untreated, symptoms of meningoencephalitis may develop. Amphotericin B and surgical debridement are the treatments of choice. Appropriate therapy reduces mortality from 100% to 17%.
Emphysematous urinary tract infections
Emphysematous cystitis and pyelonephritis are rare but dangerous complications of common urinary tract infection. More than 95% of patients with an emphysematous urinary tract infection have (poorly controlled) diabetes. E. Coli is the causative organism in 70% of cases . Emphysematous cystitis and pyelonephritis should be considered when fever persists despite adequate antimicrobial therapy. A CT scan will show gas formation in the pyelum or bladder wall. Gas formation is likely to be a result of hyperglycemia and impaired blood supply, in combination in the presence of gas forming bacteria, facilitating anaerobic metabolism. Antibiotic treatment alone is mostly sufficient for emphysematous cystitis.
Emphysematous pyelonephritis should be treated with adequate antibiotic treatment in combination with either percutaneous drainage or nephrectomy. A decade ago nephrectomy was always the first choice in emphysematous pyelonephritis. A recent meta-analysis shows that in about 70 % of cases percutaneous drainage is sufficient, and nephrectomy can be avoided. In case of pre-existent renal insufficiency or when percutaneous drainage is technically impossible, immediate nephrectomy is indicated. Mortality is between 7 and 13%, despite adequate and immediate treatment.
Emphysematous cholecystitis is a rare infection that primarily occurs in men. About 40% of all patients with emphysematous cholecystitis have diabetes mellitus. The diagnosis is usually made when conventional imaging is performed (ultrasound, x-ray or CT scan) and gas formation is found. Clostridium species, E Coli, and Klebsiella species are the most frequent causative organisms. In case of emphysematous cholecystitis, rapid cholecystectomy should be performed. In case of an unacceptably high surgical risk, percutaneous drainage can be considered. Mortality of emphysematous cholecystitis is estimated to be around 15%, compared to 4% of patients with non-emphysematous cholecystitis.
Necrotising fasciitis is a rare soft tissue infection with a very fulminant course: it is fatal in 20-40% of cases despite optimal treatment. About 70% of patients with necrotising fasciitis has diabetes mellitus. Necrotising fasciitis of the genital, perineum and perianal region is also named ‘Fourniers gangrene.’ The clinical presentation may be deceivably mild: the first symptoms are erythematous skin discoloration and low grade fever. Pain may be disproportionately severe for the physical findings. When crepitus and hematologic bullae appear a few days later, the disease is likely to be fatal.
Rapid intervention with antimicrobial treatment in combination with extensive surgical intervention is essential. Toxin producing Staphylococcus aureus, beta haemolytic streptococcus bacteria, and in selected cases vibrio bacteria are most commonly the causative pathogens.
Malignant otitis externa
Malignant otitis externa is a rare but life-threatening infection, almost exclusively associated with Pseudomonas aeruginosa. Almost all patients have diabetes mellitus, mostly in poor control. Swimming and wearing a hearing aid are other predisposing factors. Patients with otitis externa present with a swollen and painful ear, sometimes in combination with otorrhoea and hearing loss. Usually there are no signs of a systemic infection such as fever or leucocytosis at presentation.
If the infection progresses to the mastoid or skull base, nearly half of patients will develop facial nerve paralysis. Other cranial nerves may also be affected. Cranial nerve involvement is a bad prognostic sign: mortality may be up to around 50% of cases. Treatment of malignant otitis externa always includes antimicrobial treatment, and in most cases also surgical debridement. No conclusive evidence exists for the role of hyperbaric oxygen therapy. It is currently recommended that hyperbaric oxygen therapy should be reserved for the most severe cases.
Patients with diabetes are at increased risk for active tuberculosis, and this was a leading cause of death from diabetes in the early part of the twentieth century. Since the prevalence of both diabetes and tuberculosis is increasing, particularly in Africa and Asia, this ‘double burden’ is becoming a major public health issue. The WHO has set up a special working group to early detect both tuberculosis and diabetes (http://www.who.int/tb/publications/diabetes_tb.pdf).
Diabetes and tuberculosis treatment may have clinically relevant interactions . Rifampicin may worsen hyperglycemia. Tuberculostatic drugs may also aggravate diabetic complications: when treated with isoniazid, patients with diabetes should be given pyridoxine to prevent (worsening of) neuropathy. There are reports that patients with diabetes more often have drug resistant tuberculosis. This may be due to lower concentrations of anti tuberculostatic drugs possibly due to interactions between tuberculostatic and glucose lowering agents .
Urinary tract infections and asymptomatic bacteriuria
Urinary tract infections are more common in patients with diabetes. The pathogens are similar to those in the non-diabetic population, except that yeasts are more frequently found in patients with diabetes. Complications of simple urinary tract infection, such as acute pyelonephritis, sepsis, renal sepsis or even emphysematous urinary tract infections (see paragraphs above), are more common among patients with diabetes. It is therefore recommended that especially in patients with diabetes, imaging the urinary tract (CT or ultrasound) is considered when symptoms of urinary tract infections do not resolve within 48-72 hours. Longer treatment duration in patients with diabetes and urinary tract infections seems reasonable to prevent complications, although no precise recommendations concerning treatment duration are made by guideline committees.
Asymptomatic bacteriuria is two to four times more prevalent in women with diabetes. In women with asymptomatic bacteriuria and type 2 diabetes, but not in women with type 1 diabetes, the risk of developing a symptomatic urinary tract infection is increased. Treating asymptomatic bacteriuria does not reduce the odds for developing cystitis, pyelonephritis or impaired renal function, and is therefore not recommended.
Erysipelas, cellulitis and osteomyelitis
Erysipelas, cellulitis and osteomyelitis are more common in diabetes, and are frequently associated with the ‘diabetic foot’ (see Diapedia section ‘Diabetic Foot’ for more detailed description of incidence, diagnosis and treatment of this complicated, multifactorial condition.). In case of a swollen, warm and erythematous foot, one should also consider gout or Charcot osteoarthropathy, which may be difficult to distinguish from osteomyelitis using clinical features and x-ray films. MRI-scan, joint aspiration or a bone biopsy is sometimes needed to differentiate (see Diapedia section on ‘Charcot osteoarthropathy’). Antibiotic treatment of soft tissue infections and osteomyelitis does not differ for patients with and without diabetes.
Surgical infections occur 1.5 times more often in patients with diabetes. Patients with worse control have an increased risk compared to patients with good glycemic control. It remains unclear whether very strict glycemic control during hospital admission lowers perioperative infection risk. It seems likely that moderate glycemic control has the best balance between avoiding infective complicatons and hypoglycaemia, both in patients with and withut known diabetes mellitus (see Diapedia section on ‘Hyperglycaemia without diabetes’)
Patients with diabetes have a reported 20-60% increased risk for pneumonia. This risk may especially be increased in patients with type 1 diabetes, for reasons that are not fully elucidated. Pathogens such as Staphylococcus Aureus, mucor and Gram-negative bacteria such as Klebsiella Pneumoniae are more frequently found in diabetic patients compared to non diabetic patients. Some respiratory tract infections have a more protracted course in diabetes, such as infections caused by Streptococcus pneumoniae, Legionella pneumophila and influenza. During influenza season patients with diabetes are more likely to be admitted to the hospital and also are at increased risk to die from influenza compared to the non diabetic population. It is therefore recommended that patients with diabetes receive immunisation against influenza A and B. In some, but not in all countries, pneumococcal vaccination is also recommended for all patients with diabetes.
Periodontal infection occurs more frequently in patients with diabetes. Improving dental hygiene and glycemic control decreases the risk for periodontal infections. In turn, periodontal infection may also worsen glycemic control. Whether treating periodontal infection improves glycemic control, and the underlying mechanisms, are the subject of current research.
Endocarditis is not an infection that is traditionally associated with diabetes. However, endocarditis occurs four times more often in patients with diabetes. It is notable that in more than half of endocarditis cases in patients with diabetes, Staphylococcus aureus is the causative organism, compared to a about quarter of patients without diabetes. This is most likely explained by the increased occurrence of staphylococcal skin infections, which may be related to fingerprick glucose measurements or insulin injection. The increased occurrence of Staphylococcus aureus as a causative organism is a likely explanation for the worse prognosis of patients with endocarditis and diabetes mellitus.
The American Diabetes Association recommends both the use of influenza and pneumococcal vaccine in all patients with diabetes. Patients with diabetes are not at increased risk for influenza. The rationale for influenza vaccination is based on epidemiological studies that influenza has a more severe clinical course in patients with diabetes, especially patients with diabetic complications . Some studies have described diabetes as a risk factor for pneumococcal infection. However, older age may be a confounder for the relationship between diabetes and increased risk of death from pneumococcal disease. Pneumococcal vaccination is not common practice in all countries. There are no indications that the antibody response to vaccination is different in patients with diabetes mellitus.
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