DIABETES AND INFECTION
Dr. Bharat B. Trivedi
Prof. & Head department of Endocrinology.
Endocrinologist, Diabetologist.
Smt. N.H.L. Mun. Medical College, Ahmedabad-6.

Diabetes is one of the oldest diseases known to mankind. The ebers papyrus of 1500 BC mentions its symptoms and suggests treatment. In the same way infections related to diabetes are also known for long. The fateful association of diabetes mellitus and tuberculosis has been known for nearly one thousand years. At the turn of the century many diabetic patients still represent an important issue. Infection tends to occur with greater frequency and severity in diabetic patients than in non-diabetic. The occurrence of infection in a diabetic patient perpetuates a vicious cycle in which infection results in uncontrolled hyperglycemia which in turn causes further aggrevation of infections.
Diabetics are more prone for infections as compared to normal. Uncontrolled diabetes rapidly promotes infection. There is a typical association of infection with diabetes, as sugar is a good media for rapid and abundant growth of organisms and at the same time infection itself disturbs the blood sugar levels and may precipitates ketoacidosis. Such infections are responsible for complications and morbidity more frequency than would be anticipated in normal individuals. However, now-a-days due to improvement in the greater health and better understanding diabetes and with the development of most effective diagnostic techniques, earlier intervention with newer human insulins as well as availability of broad spectrum antibiotics with better tolerability, have made the results are more favorable and hence the death rates due to infections had gone down from 17.6% in preinsulin era to 8.5% in insulin era. Let us hope still some better data will come out in recent future.

WHY DIABETICS ARE MORE PRONE FOR INFECTIONS
It is said in diabetics there are certain factors which play part in this direction. Increased susceptibility to infection is in this way multifactorial. The main effect f hyperglycemia and additional immune disturbance in type I diabetics do play role. The impairment of wide range of functions in neutrophils and macrocytes (Macrophages) including chemotaxis and adherence phagocytosis and intracellular killing of microorganisms is brought by hyperglycemia. In diabetes the movement of phagocytic cells may be generally impaired.
The W.H.O. has included diabetes in its classification of secondary immunodeficiency diseases. The development of secondary immunodeficiency seems to be determined by alterations involving at generally including polymorphonuclear granulocytes and/or lymphocytic subsets activity.
Polymorph nuclear granulocytes represent the host’s first defense barrier against bacterial agents. Alternation in chemo taxis, phagocytosis, immunoglobulin production and complement functions do occur in diabetic patients. Polymorph nuclear granulocytes, cells from diabetics have a reduced chemo taxis especially when the diabetes is poorly controlled. There are two stages of phagocytosis adhesion and ingestion of microorganisms into intracytoplasmic vacuoles. An increase in sialidase enzyme secretion together with a corresponding reduction in cell membrane sialic acid may play part along with defective lactin receptors losing their capacity to recognize target and fail to initiate phagocytosis. The critical step of intracellular killing is mediated by the intracellular release of toxic free radicals, super oxides and hydrogen peroxide. This respiratory burst which is impaired in diabetics correlates with intracellular killing. This whole process is dependent on nicotinamide adenine dinucleotide phosphate (NADPH).
The NADPH is normally generated by the metabolism of glucose through the hexose monophosphate shunt and in diabetes more glucose enters the phatogocytes and is metabolized by the polyol Pathway. Aldose reductase, the rate limiting enzyme of this process requires NADPH and this is consumed when flux through polyol pathway increase. This competition for NADPH is thought to account for the reductions in the respiratory burst and in intracellular killing.
The metabolic disturbances associated with diabetes are probably important in impairing the function of polymorphonuclear cells. Once phagosome and lysosome fusion has taken place. Killing is carried out by lysosomal enzymes. A decrease in the killing capacity of polymorph nuclear granulocytes associated with high blood sugar may come to normalization within 48 hours after correction of blood sugar levels.
Several immunoglobulin levels IgG and IgA have been reported to be reduced in diabetics as compared to normal. As well as a significant reduction in the quantity and functional activity of complement components may occur in diabetic patients. Above all these local factors like underlying susceptibility to infection, vascular disease, nerve damage and increase in blood sugar may aggravate the process. This may call upon decrease circulation, hypoxia and reduction in absorption of antibiotics and proliferation of bacteria.
In type I or IDDM, genetics predisposition to infections also plays part. Along with all above factors which are abnormalities of aspects of phagocyte functions – mobilization and chemo taxis, adherence phagocytosis and intracellular killing with bactericidal activities, micro vascular circulations abnormality may result in decreased tissue perfusion. Hyperglycemia per say reduces oxidative killing capacity because of increased glucose Metabolism through polyol pathway depleting NADPH which is necessary for generation of super oxide free radicals.
In type I or IDDM, there is alteration in some lymphocyte subpopulations, a reduction in ‘T’ lymphocytes and under specifically in the number of CD4 phenotype. (‘C’ helper ‘T’ Lymphocytes) and reduction in CD4/CD8 ration serum immunoglobulin levels IgG and IgA have been reported to be reduced in diabetics compared to normal. As well as significant reduction in the quantity and functional activity of complements may occur in Diabetic patients. An underlying susceptibility of target tissues due to hyperglycemia, vascular disease and nerve damage is proved with the relative tissue hypoxia may cause proneness to infections. A reduction in antibiotic absorption due to microangiopathy may lead to persistence of infections. A reduction in antibiotic absorption due to microangiopathy may lead to persistence of infection. About 25% of IDDM subjects have this.

WHAT EFFECT INFECTION PRODUCES ON METABOLISM:
The major cause of hyperglycemic crisis is infection. It is the most common precipitation of Ketoacidosis in diabetics and it accounts for 30% of cases. Due to increase secretion of counter regulatory hormones such as glucagons, cortisol, growth hormone and catecholamine, gluconeogensis is stimulated and blood glucose levels are increased and insulin secretion is inhibited. This results in relative or absolute insulin deficiency. In NIDDM due to insulin resistance significant hyperglycemia may persist as glucose uptake in liver and skeletal muscles is impaired. The elevation of counter regulatory hormones and insulin deficiency in diabetes with infection leads to diabetic ketoacidosis and creates an emergency which should be dealt with immediately considering condition itself and infection too.
The underlying mechanism has still to be determined, but increases in circulating cortisol concentrations and in certain cytokines, secreted by immune cells in response to infection, may contribute amongst the latter are the interleukins and tumor necrosis factor a, which impair insulin action by inhibiting the tyrosine kinase activity of the insulin receptor. Here the requirement is to keep blood sugar near normal levels.

DIFFERENT INFECTIONS IN DIABETICS

1. RHINOCEREBRAL MUCORMYCOSIS
    The four genera which affect the humans are Absidia, Mortierella, Mucor, and Rhizopus. This relates to a     fulminant fungal infection. Pulmonary and alveolar variety are also very common and less common are     cutaneous, gastrointestinal (more of esophagus and fugal diarrhea) and other disseminated form.
    This fulminant variety is now-a-days seen commonly and frequently, if brain does not know eyes do not see     and brain does not record. Here the route of entry is nasopharynx and may extent upwards causing severe     headache and involvement of Para nasal sinuses may lead to bloody discharge. When orbital structures are     involved, it may lead to proptosis and loss of vision with a bad prognostic value. The diagnosis is done by     culture of biopsy of affected mucosae. Most important complications are meningoencephalitis, thrombosis of     internal carotid arteries and cavernous sinuses. Tissue biopsy show characteristic hyphae. Rhinocerebral     mucormycosis can presents as a painful soft tissue periorbital and perinasal swelling with induration and     discoloration with blood nasal discharge. Patients may come with diabetic ketoacidosis.
    The treatment consist of human insulin to get normal blood sugar, intravenous fluids and aggressive surgical     management, especially when it extents to the orbits, then radical debridement is necessary, here the     progression is rapid (in hours to a few days) and out come is usually fatal if not dealt with aggressively. It     may lead to exophthalmus, opthalmoplegia and cranial nerve palsies and meningoencephalitis. Patients may     require reconstructive surgery. Mortality remains as high as 50%.
    Tc agents, Tc hexamethylporpyleneamineoxine (HMPAO) is becoming increasingly common for white cell     scanning. Recently Tc-anti-Nca-90fab’-fragment was used. In patients with soft tissue and abdominal     infection this form of imaging has a diagnostic accuracy upto 100%. In prosthetic infection focal infection and     in acute and chronic osteomyelitis it gives accurate results. It also throws some light on successful antibiotic     therapy while comparing 99Tc infection Scan before & after treatment with antibiotics. Pulmonary     mucormycosis is also known and it mimics any chest infection, presenting with cough, fever, pleuritic pain     and haemoptysis and it should be suspected in any refractory pneumonia in diabetic patients.

2. MALIGNANT EXTERNAL OTITIS
    This condition occurs in elderly uncontrolled diabetics and is caused by a chronic infection of external auditory     meatus and leads to destruction of surrounding tissue due to pseudomonas aeruginosa. It is also known as     progressive invasive of necrotizing otitis external, high index of suspicion in diabetics, not responding for     otalgia and otorrhoea by common drugs will help, in 50% of cases. There is involvement of facial nerve.     When there is extension of infection to jugular foramen of in hypoglossal canal, the involvement of 9th, 10th,     11th, and 12th cranial nerves is quite possible. It may end up in meningitis where MRI may help in diagnosis.     Standard antibiotics like penicillin (carbenicillin) plus an aminoglycoside for a pretty long time may help with     surgical debridement monotherapy with ceftazimide as well as ciprofloxacin may work well. Involvement of     temporal bone and back of skull is common – The overall mortality in the condition is 20% and others may     land up with permanent disability.
    In my department still nine patients are coming with good diabetics control along with very good control of     this condition.
    Therapy consists of surgical debridement and a combination of carbenicillin with an amynoglycoside     continued for upto six weeks and at least one week after negative cultures to ensure no recurrence.

3. EMPHYSEMATOUS PYELONEPHRITIS
    This may follow a severe bacterial urinary tract infection. Pyelonephritis presents with loin pain, fever and     systemic upset and urinary tract symptoms often with severe disturbance of glycemic control. Most likely     definition of this entity includes a requirement for the presence of gas within the renal parenchyma which     may enter the perinephric space by extension. This is a necrotizing infection with gas production in and     around the kidney. Gas may occur in calyces, collecting system of in bladder. A plain x-ray film and     CT-    scanning without contrast may show a motted renal parenchyma with the gas bubbles and often a     radial     distribution. Usual causative organism is typical urinary pathogens like E.coli, K. pneumoniae, B.     urinabillis and E.aerogens. After giving proper antibiotics like third generation cephalosporin of ciprofloxacin     and other fluroquinolones for a sufficient period of time, if it does not respond then nephrectomy is     necessary. Intravenous insulin infusion is often required for control of hyperglycemia.

4. EMPHYSEMATOUS CHOLECYSTITIS
    This predominantly occurs in diabetics more common with the type II diabetics involving both the sexes     equally. It is a rare complication of acute cholecystitis in which air is found in the lumen and in the wall of gall     bladder with the possible extension in the pericholecystic space. In 80% of the cases diabetes is detected.     Here perforation and gangrene takes place in the gall bladder and mortality is increased. Here the     presentation is the same as pain in the right upper quadrant, nausea, vomiting and fever. During the next     48 hours gas develops in the gall bladder lumen and wall, and then extension of gas occurs. This is revealed     on radiological examination. Here the response is well with broad spectrum parentral antibiotics and early     cholecystectomy before gangrene in the gall bladder appears.

5. ACUTE NECROTIZING FASCITIS
    This is soft tissue infection which is necrotizing and spreads along the fascial tracts of planes and causes the     problem. This is also known as acute dermal gangrene. It is severe & progressive and leads to necrosis of     subcutaneous tissues down to the level of the muscle fascia but usually sparing the muscles. In North     Western Europe a sharp increase in the number of cases have taken place with invasion by group     streptococci, other Meleney’s gangrene which advances very slowly affection the skin is also known.     Involvement of the perineum and external genitalia by group A b - hemolytic streptococci of various     serotypes-most common is M1 is primarily responsible but may act together with staphylococci aureus and     epidermidis of anaerobes, including enterobacteriae.
    With proper control of diabetes with perfect dose of human insulin, high dose of intravenous antibiotics,     benzylpenicilline and clindamycin work well. Along with the early and extensive surgical debridement with     hyperbaric oxygen therapy may work.

6. INFECTION CAUSED BY THERAPEUTIC INTERVENTIONS
    Now-a-days with new devices of insulin injections, the problems of boiling the needle and syringes have     gone away and the occurrence of finger bed infection and abscess have decreased, when patients take     insulin by themselves and with newer devices like disposable insulin syringes and Novopen, and Humapen,     occurrence of infection and abscess formation have gone down and occurs in few cases.
    Impotency is higher in the diabetics than their counter parts non diabetics. Along with other therapies penile     prosthesis are very common. The chances of infection are seen as early as 2 week of as late as 2 years after     implantation, staphylococcus epidermidis is the infection organism in 40 to 50% of the cases. Immediate     therapy consists of the removal of prosthesis and therapy with broad spectrum antibiotics and the post     operative drainage.
    As compare to non-diabetics the infection rate is higher among diabetics undergoing organ transplantation     e.g. kidney, heart transplantations.
    Continuous ambulatory peritoneal dialysis is all increasingly common modality of therapy in end stage renal     disease in patients with diabetes. This also carries a risk of infection like any indwelling foreign body in the     diabetics. Also many diabetics with end stage renal disease undergo heamodialysis through subclavian or     femoral catheter kept in situ for days or months. These are also prone for infections. Arterio venous grafts     can also be infected by haematogenous spread of microorganism form a distant site of infection,     staphylococcus aureus is estimated to cause 80% of infection. All above infections need proper antibiotics for     adequate time period. Occasionally a surgical approach is required.
    
    

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