CHRONIC KIDNEY DISEASE – DEFINITION AND STAGING, ETIOLOGY, NATURAL HISTORY AND PROGRESSION, CLINICAL MANIFESTATIONS, DIAGNOSIS AND MANAGEMENT

GENERAL CHARACTERISTICS

Chronic kidney disease (CKD) is an important public health problem affecting more than 10% of the general population. CKD is an important risk factor progressing to end stage renal disease (ESRD), cardiovascular disease and premature mortality. Management of ESRD is expensive and beyond the reach of many sections of the population in developing countries. CKD is a silent disease and if not detected and treated early, may progress to ESRD. Hence, it is important to identify CKD early and institute measures to retard its progression.

DEFINITION AND STAGING

Chronic kidney disease is defined as either kidney damage or GFR <60mL/min/1.73m2 for >3 months. Kidney damage is defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies.

CKD is characterized by kidney damage characterized by structural, functional or pathological abnormalities in the kidney associated with abnormalities in the composition of urine and/or blood of more than 3 months duration. Anomalies in the imaging tests and decrease in the GFR may be demonstrable. If the GFR is less than 60 mL/min/1.73 m2 body surface, persisting for more than 3 months, this by itself can constitute CKD.

STAGES OF CHRONIC KIDNEY DISEASE

Stage                Description                                           GFR (mL/min/1.73m2)                     

1.                    Kidney damage with normal                                > 90

                       or increased GFR

2.                    Kidney damage with mild                                   60-89

                       decrease in GFR

3.                    Moderate decrease in GFR                               30-59

4.                   Severe decrease in GFR                                   15-29

5.                   Kidney failure                                                < 15 or dialysis

Staging

Stage 1 CKD represents kidney damage when GFR is normal or high. This includes patients with albuminuria or those with abnormal imaging studies.

In stage 2 CKD, there is evidence of kidney damage with mild decrease in GFR (60- 89 mL/min/1.73 m²). In the absence of kidney damage, this level of GFR per se, does not constitute CKD.

Stage 3 CKD includes patients with moderate decline in GFR (59-30 mL/ min/ 1.73 m²). All patients with GFR of less than 60 mL/min/1.73 m² are classified as having CKD irrespective of whether kidney damage is present or not. This is the stage where serum creatinine starts to rise. Majority of patients still remain asymptomatic. Nocturia and polyuria are early symptoms that may appear at this stage.

In stage 4 CKD, the fall in GFR is severe (29-15 mL/min/1.73 m²). Overt uremic symptoms like loss of appetite, nausea, anemia and recurrent infections occur during this stage.

Stage 5 CKD is the stage when GFR is less than 15 mL/min/ 1.73 m². At this stage the patient usually requires dialysis or other forms of renal replacement therapy.

GFR is the best measure of overall kidney function in health and disease. GFR can be affected by chronic kidney disease which reduces the number of nephrons. Hemodynamic factors affect single nephron GFR and they result in fall in the GFR. The normal GFR of a young adult is around 120-130 mL/min/1.73 m². Normal values in women are 8% lower from those of men at all ages. Above the age of 30 years, GFR declines at the rate of approximately 1 mL/min/1.73 m² per year.

ETIOLOGY

The causes of CKD are broadly classified as given below.

Glomerular Diseases

Primary—Focal segmental glomerulosclerosis (FSGS), IgA nephropathy, membranoproliferative glomerulonephritis (MPGN)

Secondary—Diabetes, systemic lupus erythematosus (SLE)

Tubulointerstitial diseases—Reflux nephropathy, obstructive uropathy.

Vascular diseases—Hypertensive nephrosclerosis, ischemic nephropathy

Cystic diseases—Autosomal dominant and recessive polycystic kidney disease (ADPKD and ARPKD)

Heredofamilial—Alport’s syndrome

Diseases in the transplant -Chronic allograft nephropathy

Age, ethnicity and distribution of renal diseases may be different in various geographical regions. Diabetes and hypertension are the two most important causes of CKD worldwide. In the developing countries chronic glomerulonephritis and chronic interstitial nephritis are relatively more common than in the developed countries.

FSGS, IgA nephropathy, reflux nephropathy and congenital anomalies of the urinary tract lead to CRF usually before the age of 40 years. Diabetes, hypertensive nephrosclerosis, ischemic nephropathy, multiple myeloma, analgesic nephropathy and systemic vasculitis are more common above the age of 55 years.

NATURAL HISTORY AND PROGRESSION OF CKD

Many diseases can intiate kidney injury and lead to progression. Reduction in the number of functioning nephrons lead to hypertrophy and increased glomerular filtration by the surviving nephrons. Glomerular hyperfiltration initially maintains GFR but later, the overworked nephrons succumb to the increased workload and lead to proteinuria, which causes further damage to the glomeruli and the tubulo-interstium. The extent of tubulo-interstitial damage is an important factor determining disease progression. Hypertension which is present in over 90% of cases of advanced CKD leads to further progression of the disease, if not controlled. Hyperglycemia also causes structural and functional changes in the glomeruli leading to progressive renal failure. Progressive destruction of nephrons leads to several adaptive mechanisms which enable the remaining nephrons to maintain body homeostasis. Though these adaptive changes are beneficial, later, they lead to maladaptive consequences. For example, early in the course of renal failure, loss of nephrons result in reduction of phosphate excretion and lead to hyperphosphatemia.

This causes a fall in serum calcium due to its binding to the excess phosphorus. Hypocalcemia stimulates PTH which results in reduction of tubular reabsorption of phosphate and increased phosphorus excretion. This helps to normalize serum phosphate levels. With progressive loss of nephrons, higher and more sustained levels PTH develop leading to secondary hyperparathyroidism with all its adverse consequences. The nature of the primary kidney disease and its activity also dictates the progression. The rate of progression of glomerular diseases is faster than that of tubulo-interstitial diseases.

CLINICAL MANIFESTATIONS OF CKD

Renal impairment is associated with a variety of signs and symptoms that are collectively referred to as the uremic state. The symptomatology may involve any system of the body. However, there is no correlation between the development of symptoms and the severity of renal disease. The early stages of CKD are usually asymptomatic and are detected only on investigations.

Edema

Most of the glomerular diseases are associated with edema. In chronic glomerular disorders, development of intermittent edema and hematuria indicates disease activity. In disorders that are not primarily due to glomerular disorders, as in most tubulointerstitial diseases, edema appears late.

Hypertension

Hypertension is the most common manifestation and it may appear early during the course of renal disease (90% in glomerular and 30% in tubulointerstitial diseases). If untreated, it leads to further damage. Rarely, uncontrolled hypertension can lead to precipitous and irreversible reduction in GFR. Hypertension is also an independent risk factor for cardiovascular morbidity.

Cardiovascular Manifestations

Cardiovascular manifestations include left ventricular hypertrophy (LVH) due to hypertension and anemia, ischemic heart disease, congestive cardiac failure due to fluid overload and myocardial dysfunction due to uremia (uremic cardiomyopathy). Electrolyte disturbances, particularly hyperkalemia can lead to bradycardia, syncope and cardiac arrythmias. Other manifestations include premature atherosclerosis, vascular calcification due to secondary hyperparathyroidism and pericarditis. Pericarditis presents with chest pain. Loud pericardial friction rub is audible on auscultation. Sometimes, fibrinous pericarditis may lead to pericardial effusion and cardiac tamponade. CKD is a major risk factor for cardiovascular disease and even mild impairment of renal function can lead to cardiovascular morbidity and mortality. Conversely, compromise in cardiac function worsens renal function too.

Gastrointestinal Manifestations

The GI manifestations like anorexia, nausea, vomiting, dyspeptic symptoms, constipation or diarrhea usually appear in Stage 4 CKD (GFR between 15 and 30 mL/min). The symptoms are mainly due to gastrointestinal mucosal ulcerations. Uremic stomatitis with dry mucous membranes, multiple small oral ulcers and parotitis are seen in advanced uremia. Rarely, gastrointestinal hemorrhage may occur. ‘Uremic fetor’ describes the ammoniacal odor occurring in patients with advanced renal failure and it is due to the hydrolysis of urea in saliva by bacterial urease. Intractable hiccoughs may occur in advanced uremia. Severe abdominal pain and paralytic ileus may occur as a result of hypokalemia. Ascites may occur in advanced renal failure.

Neuropsychiatric Manifestations

Paresthesias, sensory or motor peripheral neuropathy, pruritus, restless legs syndrome and bladder dysfunction are the neurologic manifestations. Subtle to gross behavioral abnormalities such as anxiety, depression, personality changes and disturbances of sleep are the psychiatric manifestations.

Flapping tremor (asterixis) and myoclonic jerks are features of uncontrolled uremia. Rarely, convulsions and coma may occur. When a patient is initiated on dialysis, abrupt and rapid removal of urea from the blood may lead to higher concentration of urea in the brain since it does not cross the blood-brain barrier rapidly. This leads to cerebral edema and transient neuropsychiatric manifestations, collectively called ‘dialysis disequillibrium syndrome’. This can be prevented by adjusting the initial few sessions of dialysis so as to achieve very gradual fall in blood urea. Patients on long term dialysis may develop features of dementia

and this is attributed to aluminum intoxication which may occur due to intake of aluminum containing antacids or through the water used for dialysis. This is no longer a major problem at present because of water treatment which involves removal of contaminants like aluminium in dialysis water and withdrawal of use of aluminum hydroxide as a phosphate binder.

Cutaneous Manifestations

The characteristic sallow complexion in renal failure is due to pallor and the deposition of yellowish brown urochrome pigment. Recurrent skin infections, dry scaly skin with severe itching, rashes, erythema, vesicles and ulcerations are common. Cutaneous calcification in association with secondary hyperparathyroidism contributes to the severe itching. Pruritic hyperkeratotic papular eruptions or Kyrle’s disease occurs in diabetics. In stage V CKD, precipitation of urea on the surface of the skin gives rise to ‘uremic frost’. Bleeding into the skin and mucosa may occur as a result of platelet dysfunction. Nail changes include pitting, burrowing and ‘half and half’ nails. In half and half nail, the distal half of the nail is pink or brown and the proximal half is white or pale. The conjunctival deposition of calcium leads to redness and gritty feeling in the eye also called the ‘uremic red eye’ while deposition of calcium as a band in the lamina propria of the cornea leads to ‘band keratopathy.’

Hematological Manifestations

Anemia is common in chronic kidney disease. It appears when the GFR is below 50 mL/min (Stage 3 CKD) and progressively worsens as GFR declines further. Symptoms appear much later, (stage 4 CKD). Usually the anemia is normocytic normochromic. The most important cause is decreased secretion of erythropoietin (EPO). Other factors, apart from EPO deficiency which contribute to renal anemia include the following.

1. Circulating uremic toxins – bone marrow resistance to the effect of EPO.

2. Reduced RBC survival (120 days to 80 days) probably due to mild hemolysis.

3. Platelet dysfunction – Bleeding, including occult gastrointestinal blood loss.

4. Iron deficiency.

5. Hyperparathyroidism – bone marrow suppression or fibrosis.

6. Folic acid deficiency.

7. Chronic inflammation.

8. Aluminum toxicity (rare).

Prolonged anemia can lead to worsening of renal function and lead to left ventricular hypertrophy and increased myocardial oxygen demand. Disturbances in the coagulation system and platelet dysfunction are common in advanced uremia. Platelet dysfunction occurs due to factors like retention of uremic toxins, nitric oxide and hyperparathyroidism.

Skeletal Abnormalities – Renal Osteodystrophy

As renal failure progresses, hyperphosphatemia, hypokalemia and secondary hyperparathyroidism develop leading to skeletal abnormalities. Renal tubular defects and altered vitamin D metabolism also contributes to skeletal changes of renal osteodystrophy. Stunting of growth, bone deformities and rickets occur due to end organ resistance to hormones as a result of circulating uremic toxins. Adults with advanced CKD manifest with high turnover bone disease (due to hyperparathyroidism), low turnover bone disease (due to vitamin D deficiency or aluminum toxicity) or adynamic bone disease (due to excessive suppression of PTH). Skeletal deformities are more pronounced especially in children. These manifest even before there is significant reduction of GFR. This is called non-uremic renal osteodystrophy. This is caused by renal tubular acidosis and disturbances in Vitamin D metabolism. With advancing renal failure, bone disease and growth retardation become more evident. Short stature is an important feature of chronic kidney disease of childhood. Uremic toxins and end-organ resistance to growth hormone/insulin like growth factor have been implicated. Prolonged use of corticosteroids may also contribute to growth retardation.

Children with advanced chronic renal failure caused by chronic tubulointerstitial and glomerular diseases also develop severe rickets with deformities (Uremic renal osteodystrophy). In adults, the most common skeletal disturbance is hyperparathyroid bone disease (osteitis fibrosa) characterized by increased osteoclastic bone resorption. This is known as high turnover bone disease. Typical radiographic features include subperiosteal resorption in the phalanges, ‘salt and pepper” pattern in the skull, vascular calcifications in peripheral arteries like radial and femoral arteries and osteosclerosis (rugger jersey spine). Large osteoclastic tumours may be seen (brown tumours) in the skeleton around weight bearing areas. A rare and unusual syndrome in patients with severe osteitis is calciphylaxis. This is due to extra-osseous calcium deposition in soft tissues. It manifests as painful violaceous mottling of the skin followed by progressive gangrenous ulcerations at the fingers, toes and ankles. Osteomalacia is the second pattern of bone disease seen in chronic kidney disease. Vitamin D deficiency and/or aluminum intoxication occurring in those receiving long-term hemodialysis aggravate this condition. It is characterized by severe bone pain, recurring fractures and proximal myopathy. In some cases, a mixed pattern of hyperparathyroidism and osteomalacia may be found. In addition, adynamic bone disease is being increasingly recognized. It is a histological diagnosis showing lack of bone formation and resorption. It is probably due to excessive suppression of PTH by calcium supplements and Vitamin D therapy.

Respiratory Manifestations

Patients with advanced kidney disease may develop dyspnea due to pulmonary edema, pleural effusion or severe metabolic acidosis. Flash pulmonary edema occurs in patients with renovascular diseases due to accelerated hypertension. ‘Uremic lung’ may be seen radiologically as a butterfly shadow in the area of the hilum and this is due to noncardiogenic pulmonary edema associated with increased pulmonary capillary permeability and exudation of proteinaceous fluid into the alveoli. Uremic serositis may present as pleurisy with associated pleural friction rub or underlying hemorrhagic pleural effusion.

DIAGNOSIS

Often CKD may go unnoticed until renal failure is advanced. Strong clinical suspicion and appropriate investigations are essential for early diagnosis. The diagnosis is established by demonstrating decreased GFR or markers of kidney damage. Estimation of serum creatinine and a creatinine clearance are usually used for this purpose.

Markers of kidney damage include proteinuria, hematuria or abnormalities of urinary sediment. Since elevation of serum creatinine occurs only when GFR is below 50% of normal, early detection of CKD depends on the other markers.

Detection of more than 5 erythrocytes per high power field in a freshly voided specimen of urine indicates significant microscopic hematuria if present on repeated examinations. Presence of dysmorphic RBCs and acanthocytes in urine usually indicates pathology in the glomerulus. Coexistence of proteinuria and cellular casts points to renal parenchymal disease. Urinary specific gravity and osmolality may be relatively fixed at around 1010 and 290 respectively, signifying the inability of the kidneys to concentrate or dilute urine. Low serum calcium, high serum phosphorus with high serum alkaline phosphatase is often seen in advanced kidney disease. Serum bicarbonate is often reduced as a result of metabolic acidosis. High anion gap is due to decreased ammonium ion production and decreased excretion of hydrogen ions. Serum levels of sodium are usually normal until renal failure is very advanced. The ability of the kidney to maintain serum potassium homeostasis is preserved till the patient is in stage IV CKD. Hyperkalemia may set in early in patients consuming excessive potassium in diet and those taking potassium sparing diuretics, ACE inhibitors or angiotensin receptor blockers (ARBs).

X-ray of the skeleton may show features of renal rickets in children or osteomalacia, osteitis fibrosa or osteosclerosis in adults. Presence of smaller kidneys detected by ultrasound imaging suggests long standing kidney disease. The exceptions to this rule include diabetes mellitus, multiple myeloma, polycystic kidney disease and obstructive uropathy. Demonstration of scarring of the kidneys may be the earliest indicator of parenchymal damage in diseases like reflux nephropathy. Asymmetry of the kidneys on ultrasound examination may be an indicator of underlying renovascular disease. Calcification and stone disease may be demonstrated by plain X-ray KUB or by ultrasound. Doppler imaging of the kidneys and renal blood vessels helps to detect renovascular disease early.

MANAGEMENT OF CHRONIC KIDNEY DISEASE

All patients require conservative management in the early stages. When the patient approaches Stage V CKD, renal replacement therapy has to be introduced.

The general management consists of:

1. Treatment of reversible causes.

2. Preventing or slowing the progression of the renal disease.

3. Treatment of the complications of renal dysfunction.

4. Identification and adequate preparation for renal replacement therapy.

CHLAMYDIA (Psittacosis/Parrot Fever) – General Characteristics, Life cycle, Definition, Epidemiology, Pathology, Clinical Features, Diagnosis, Treatment and Control

General Characteristics

Chlamydiae are small gram-ve organisms which remain intracellular. They have both DNA and RNA. They possess cell wall and divide by binary fission. They have a unique biphasic life cycle with dimorphic forms which are functionally and morphologically distinct.

Life Cycle

The elementary body (EB) is an infectious but metabolically inactive form which attaches to the epithelial cell surface and enters the cell by endocytosis. Once endocytosed it differentiates into a larger pleomorphic form called reticular body (RB) and remains inside a membrane bound vacuole thereby evading phagolysosomal fusion.

Once inside the cell they interrupt the metabolic processes of the host cells and utilize them for their own metabolism and replication. These processes are not yet fully understood. Antigenically they are complex, possessing antigens of genus, species and serotype specificity. The human pathogens include the species Chlamydia trachomatis, Ch. pneumoniae and Ch. psittaci.

PSITTACOSIS (PARROT FEVER)

Definition

Psittacosis is an infectious disease caused by the organism Chlamydia psittaci which is a primary pathogen of birds. Chlamydia psittaci is a gram-negative obligate intracellular parasite.

Epidemiology

The disease is present all over the world. Psittacine birds (parrots, parakeets, cockattoos) are commonly affected, but all types of birds may suffer. Infection in man results from close contact with birds. The organism is present in the feces of infected birds. Humans acquire the infection by inhalation of bird’s feces or handling the tissues of infected birds.

Pathology

Chlamydia psittaci reaches the pulmonary alveoli and the reticuloendothelial cells of the spleen and the liver. In the lung patchy consolidation develops. Liver and spleen are enlarged due to congestion. The heart, meninges, and the brain also show congestion. The alveolar exudate is mainly mononuclear.

Clinical Features

The average incubation period is about ten days. The onset is sudden with fever, malaise, sore throat, and intense photophobia. Temperature ranges from 37-39°C. There is relative bradycardia. Tachypnea may occur. There may be cough with scanty mucopurulent sputum. Signs of pulmonary consolidation may be evident. After about 10 days of fever the temperature comes down by lysis. Mortality may reach 20%. Respiratory failure and toxemia are the usual causes of death.

Diagnosis

Psittacosis has to be differentiated from viral pneumonia, typhoid fever, influenza and Q fever. History of contact with birds is the most helpful clue to diagnosis. In the first few days of the illness the organisms can be isolated from the sputum and blood by inoculation into mice or into the yolk sac of embryonated eggs or into irradiated cell cultures. Diagnosis can be established by demonstrating antibodies by ELISA or microimmunofluorescence.

Treatment

Tetracycline is very effective. It is given in a dose of 4 g/day for 2 days and then 2 g daily till recovery is complete. Doxycycline 100 po bd up to 3 weeks is a convenient alternative.

Control

Quarantine of birds imported from other countries should be insisted upon and the infected birds should be killed. Carrier state among the birds is reduced by incorporating tetracycline in bird feeds

CHILDHOOD AUTISM – Definition and General Characteristics

The term autism denotes a state of absorption into ones own world of phantasy with loss of contact with the reality. Reported incidence of childhood autism is 2-5/10,000 live births.

 Childhood autism was originally described by Leo Kanner in 1943 as Early Infantile Autism. Autistic aloneness, language abnormality and restricted and compulsive behavior are the main three features of this disorder. Boys are more affected than girls. The disorder is unmasked by the third year of life. The child is abnormally quiet, lacks the usual emotional warmth and likes to be left alone. Eye-to-eye contact is avoided. He does not communicate through conversation. Pronouns are reversed. ‘You’ is used to mean ‘I’ Echolalia is common. Words and behavior are stereotypic. The child is fond of sameness in everything. Bizarre behavior such as rocking, whirling the head and flapping of hand may be present. Impulsive violence is common. The arithmetic skill is relatively high. IQ may be around 70 in most cases. Some have normal IQ. Many cases may be attributable to birth trauma. Autism is strongly a genetic disorder, and probably arises from multiple genetic defects. Recurrence within families with one affected child is high.

There is no specific treatment. Antipsychotics are given to control violence and hyperactivity. Behavior therapy may be helpful. Parents are to be counseled regarding management of the child at home. Many improve spontaneously and may be able to attend normal school. A few may require training in special schools. Some require special residential care.

CHIKUNGUNYA – Etiology, Distribution and Incidence, Transmission and Epidemiology, Clinical Features, Course and Prognosis, Diagnosis, Treatment, Prevention and Control

General Characteristics

Chikungunya (CHIK) fever is an acute infective disease, characterized by symmetric polyarthropathy, fever, rash, and rarely, generalized hemorrhages and CNS symptoms. The disease derives its name from the sudden onset of severe joint pain, which cripples the victim. The disease was first described in 1955 following an outbreak in Africa in 1952.

Etiology

CHIK virus is an alphavirus in the Semliki Forest complex (Togaviridae) and most closely related to o’nyong nyong(ONN) virus.

Distribution and Incidence

CHIK is widely distributed in Africa, the middle east, and Asia. The disease has now become endemic in several parts of India. In recent years as extensive epidemic affected several African and Asian countries, affecting millions of people. It is possible that the original virus has undergone genetic mutation.

Transmission and Epidemiology

In India, Aedes aegypti mosquito is the main vector. Aedes albopictus is also implicated. In Africa there is a sylvian cycle involving forest mosquitoes, humans and possibly other mammals. In Asia, sylvatic viral reservoirs have not been defined.

CLINICAL FEATURES

The incubation period varies from 2-10 days, usually 3-7days. The onset is sudden with abrupt fever (above 40oC), chills and rigor, headache,  body pains and joint pains. There may be mild conjunctivitis, pharyngitis an erythematous rash over the body and face. The joints may be so inflamed that normal activities, standing and walking become painful. Arthropathy is symmetric, affecting the extremities and less often the shoulders and hips. Definite joint effusion is seen in 10% of cases. Small joints of the hands and feet and major joints of the lower limbs are affected most. Pain may be excruciating, crippling the patient quite out of propotion to the general disability. Fever and joint pains persist for up to six days after which they subside. Residual arthropathy lasting for months may occur in up to 30% of adults; especially in elderly patients. Morning stiffness and pain may persist for even a few months. Pre-exsisting joint problems and neurological disorders considerably worsen the disability and delay recovery. Joint pains are milder and may be even entirely absent in children.

A faint maculopapular rash may appear concurrently with defervescence. Complications such as hyperpyrexia, hemorrhagic manifestations, encephalitis, polyneuropathy of the Guillain-Barré type and ECG chages suggestive of myocarditis were recorded in the Madras outbreak. Hyperpyrexia caused death in one patient. Among asymptomatic subjects 38.4% showed hemagglutination (HI) antibodies to chickungunya virus, confirming the presence of the virus in the community.

Hemorrhagic manifestations occur occasionally. CNS manifestations like meningism, convulsions and acute polyneuropathy has been reported in a minority of patients, especially children and infants.

Course and Prognosis

The diseases many run a benign course with slow recovery even if untreated. Arthropathy may persist for varying periods and can be disabling. The acute illness in children and infants and elderly persons can be fatal. The primary role of uncomplicated chickungunya as a cause of death is not established. It produces considerable morbidity and impairment of the quality of life for prolonged periods.

Diagnosis

Routine laboratory investigations are not specific. The ESR may be elevated to 20-50 mm/hr and CRP may also be elevated. Isolating the virus or identifying genomic products by PCR in acute phase blood specimens can confirm the diagnosis. Serologically specific IgM or other antibodies can be demonstrated by IgM capture ELISA test. This test will distinguish the condition form dengue which is also transmitted by the same vector.

Treatment

Rest and symptomatic treatment with non-steroidal anti-inflammatory drugs give relief. Prolonged arthropathy demands symptomatic treatment. Chloroquine given in a dose of 250 mg od or bd has been reported to be useful. In any case results are not impressive.

Prevention and Control

An experimental live attenuated vaccine has been shown to produce high levels of neutralizing antibody in human volunteers but efficacy has not been tested. Anti-mosquito measures and personal protection with mosquito repellants will reduce the spread.

CANDIDIASIS – General Characteristics, Diagnosis and Treatment

General Characteristics

Candida albicans is a common inhabitant of the oropharyngeal, genital and intestinal cavities of man. Candidiasis is infection by Candida albicans. In most of the cases it remains as a local infection affecting the skin or mucous membranes of the mouth or genitalia. In the mouth it presents as oral thrush which is seen at the extremes of ages, those on antibiotic therapy or in immunosuppressed individuals. In the genitalia it usually presents as vulvovaginitis in diabetic women who are not well-controlled. Cutaneous candidiasis usually affects the intertriginous areas.

Systemic candidiasis occurs in immunocompromised individuals and in drug addicts who share needles. The fungus becomes invasive and spreads through the blood stream to produce several lesions.

1. Localized lesions: Urinary tract, liver, heart valves, meninges and peritoneal cavity.

2. Widely disseminated: Associated with septicemia (candidemia). In disseminated candidiasis also the main targets of attack are the kidneys, brain, liver, gastrointestinal tract, eye (endophthalmitis) and heart valves.

Extensive, recurrent and persistent oropharygeal and esophageal candidiasis is a common AIDS associated infection.

Diagnosis

The organism can be demonstrated microscopically by examining samples from local lesion. In tissues, PAS staining or methenamine silver staining reveals the organism.

The fungus can be grown in Sabouraud’s medium. Antibodies to Candida can be detected by ELISA or immunodiffusion. The candidal antigen can be demonstrated by ELISA or radioimmunoassay.

Treatment

Amphotericin B, fluconazole, ketoconazole and itraconazole are all effective in appropriate dosage to control the systemic infection. Local surgical therapy should be aimed at removal of the source of infection.

Dose: Amphotericin B up to 50 mg/day IV for 1-2 weeks and more.

Fluconazole 400 mg/day.

Ketoconazole 400 mg/day for several weeks.

Itraconazole 200-400 mg/day.

Itraconazole and fluconazole are less adrenosuppressive compared to ketoconazole. Superficial skin and mucous membrane lesions respond well to nystatin  ointment or nystatin mouth washes. Fluconazole given orally is very effective to cure vaginal candidiasis.

BRONCHIAL ASTHMA – General Characteristics, Pathology, Clinical Features, Diagnosis, Treatment and Prevention

General Characteristics

The term ‘asthma’ in Greek means ‘breathless’ or ‘breathe with open mouth.’ Asthma is a common chronic inflammatory condition of the airways whose mechanism is not completely understood yet. Epidemiological studies suggest that multiple genetic and environmental factors contribute to the causation of asthma, a clinical condition that is viewed as a cluster of related disorders. Genetic factors contribute to the variability with regard to age of onset, sensitivity of environmental causes and response to treatment.

Airway inflammation is associated with airway hyperresponsiveness, airflow limitation, and respiratory symptoms. Airway inflammation leads to limitation of airflow by acute bronchoconstriction, edema of the airway wall, formation of mucus plugs, and airway remodelling.

The tracheobronchial tree reveals increased responsiveness to immunological and non-immunological factors. Several organic dusts, fumes, and chemicals precipitate immunological mechanisms. Non-immunological stimuli include thermal, chemical or psychological factors.

Bronchial asthma used to be classified into the extrinsic (atopic) and intrinsic (cryptogenic) types. In the former an external precipitating factor is identifiable, whereas in the latter, it is not. The antigens include ingested, inhaled or parenterally administered substances.

The serum of such individuals may show elevated levels of specific antibodies belonging to the IgE and sometimes IgG classes. Persons developing extrinsic asthma have other atopic manifestations like eczema. The dermatological and respiratory manifestations show a see-saw relationship. In many cases family history of bronchial asthma may be present. Extrinsic asthma generally sets in by the age of 10-15 years. This type has a better prognosis from the point of response to therapy and mortality. The age of onset for intrinsic asthma is after 30 years. Precipitating causes or raised antibody levels are not evident but these patients show a higher frequency of eosinophilia, aspirin sensitivity, and nasal polyposis. Common stimuli which precipitate extrinsic asthma are inhaled allergens like house dust, pollens, fungi, animal hairs, insect scales and industrial fumes, and foods and drugs which are consumed in day-to-day life. Once sensitization occurs, these antigens release chemical mediators from the mast cells by interacting with the IgE molecules on their surface. Type I hypersensitivity reaction ensues. Asthma can also be caused by Type III (delayed) hypersensitivity mechanism mediated by IgG. In some individuals both Type I and Type III reactions occur, the former leading to an immediate asthmatic paroxysm and the latter leading to a delayed episode.

Exercise-induced asthma is a problem in children and young adults, in which bronchoconstriction is provoked by various forms of exercise such as running or climbing stairs, but others such as swimming may not do so. Provocation of bronchoconstriction by cold inspired air is a possibility in such cases. In many cases the attacks are brought on straight by the exercise, but in the others asthma sets in several hours after the exercise. The mechanism is a Type I hypersensitivity reaction. Short acting β2-agonists are used to prevent exercise- induced asthma. Inhaled steroids are indicated and are useful. Systemic steroids are seldom necessary.

PATHOLOGY

Inflammation of the airways is brought on by several factors. Eosinophils, T-lymphocytes (CD4+), macrophages and mast cells infiltrate the bronchial wall. The epithelium is vacuolated and the ciliated cells desquamate. Several cellular factors play their roles in the inflammatory process. Neuropeptides such as bradykinins, substance P and neurotensin A lead to bronchoconstriction and excessive secretion of mucus.

The main chemical transmitters, which alter the airways, are histamine, prostaglandin and leukotrienes. These lead to contraction of bronchial muscle, increase in vascular permeability and excessive secretion of abnormal mucus. Airway inflammation persists for several years. Its severity correlates with the severity of asthma. Hyperresponsiveness of the inflamed airways is aggravated by autonomic and neural mechanisms. The final result is obstruction of the small and medium sized airways brought about by mucosal edema, tenacious mucus and bronchoconstriction.

CLINICAL FEATURES

The attacks start with dyspnea (often at rest), expiratory wheeze, and cough. The onset is abrupt in most cases. These attacks may occur seasonally or during all times of the year (perennial asthma). The attacks may last for several hours if untreated. Severity of the paroxysm varies. In the moderately severe case the patient is orthopneic and cyanosed, and the accessory muscles of respiration are active. There may be ineffective cough with only very scanty and tenacious mucoid expectoration. The asthmatic paroxysm in many individuals is ushered in by a bout of coughing and sneezing on exposure to the allergen. The pulse is rapid. Blood pressure is normal or elevated. In severe cases  pulsus paradoxus may occur. Expansion of the chest is considerably diminished, often to less than 2 cm during the attack. The diagnostic feature of bronchial asthma is the presence of expiratory wheeze heard all over the chest.

DIAGNOSIS

Diagnosis of bronchial asthma is clinical. The history of sudden attack of paroxysmal dyspnea, cough, and the auscultatory hallmark of expiratory wheeze heard all over the chest are diagnostic. Long duration of complaints, history of allergy, and positive family history are other helpful clinical points.

Clinical features which indicate severe ventilatory Impairment

1. Inability to narrate history continuously or severe distress even on mild exertion,

2. Cyanosis, flapping tremors,

3. Mental confusion,

4. Respiratory rate above 25/minute,

5. Heart rate persistently above 110/minute.

6. Inspiratory fall in blood pressure exceeds 16 mm Hg,

7. PEFR less than 40% of predicted value, and

8. Feeble breath sounds.

Differential diagnosis:

Bronchial asthma has to be differentiated from other causes of paroxysmal dyspnea. These include chronic bronchitis emphysema syndrome (CBES), acute left-sided heart failure, acute bronchitis, tropical pulmonary eosinophilia, metabolic acidosis, and tracheal obstruction by foreign bodies or tumours.

It is important to distinguish left-sided heart failure (cardiac asthma) from bronchial asthma. Left-sided heart failure complicates valvular heart disease, systemic hypertension or ischemic heart disease. It causes paroxysmal dyspnea in the first half of the night whereas bronchial asthma is more common in the early hours of the morning.

In bronchial asthma there is generalized wheeze all over the chest, whereas in cardiac failure, basal crepitations are more prominent, though generalized bronchospasm may also be evident at times. In heart failure, gallop rhythm may be evident. Careful search for the underlying disease may reveal the etiology.

TREATMENT

Treatment may be described under three heads: (1) treatment of the acute attack; (2) treatment in between attacks; and (3) treatment of acute severe asthma.

TREATMENT OF THE ACUTE ATTACK

At present the drugs of choice employed to stop an acute attack are beta 2-agonist drugs. They act mainly on the bronchial muscle as relaxants without much effect on the cardiovascular system. These include salbutamol, terbutaline, salmeterol, bambuterol and others. These can be given orally, as inhalations (aerosol or powder) or parenterally. The oral dose is effective within 15-20 minutes and the action lasts for 4-6 hours.

Nebulizers, which can be carried by the patient or operated in the emergency room, are available for administration of these drugs. These can deliver larger doses as required. The drug solution is nebulized by passing oxygen or air under pressure through it.

PREVENTION

It is important to avoid known allergens, which can be identified. In the case of some allergens like house dust and pollen, desensitization can be achieved by repeated challenges.

Inhaled corticosteroids 200-800 micro g per day has been recommended as the treatment of choice for regular preventive therapy of asthma.

Yoga and controlled breathing exercises are of considerable benefit in allaying the paroxysms.

BARBITURATES – General Features, Clinical Features and Treatment

GENERAL FEATURES

Till recently, barbiturates were the most common drugs used for suicide. Accidental poisoning is seen in epileptics, psychiatric patients and children who get regular prescription for these drugs.

The most widely used barbiturate is phenobarbitone and it is used as an anticonvulsant. Absorption and metabolism of phenobarbitone are slow. About 10% of the drug is excreted in urine unchanged. The lethal dose for adult is about 5 gm. Simultaneous administration of alcohol aggravates its effects.

CLINICAL FEATURES

Central nervous, respiratory and cardiovascular systems are affected the most. Drowsiness, slowing of respiration and hypotension follow. Pupils are small and react to light.

In severe poisoning, when medullary centers are depressed, the pupils are dilated and fixed, which indicates a poor prognosis. Tendon reflexes are sluggish or absent. Necrosis of sweat glands and bullous lesions over the skin develop in a few as a hypersensitive reaction. These lesions heal slowly.

Diagnosis can be confirmed by detection of barbiturates in the gastric contents and estimation of barbiturate in blood.

Treatment

In addition to general measures, forced alkaline diuresis and dialysis are helpful. Bemegride (megimide) is considered to be a specific antidote but subsequent research has disproved this assumption.

Repeated doses of activated charcoal and hemoperfusion are the modalities described. Since pneumonia is a fatal complication, these patients should be observed for a week till recovery is complete.

AVIAN FLU (INFLUENZA GROUP A H5N1 VIRUS) – General Characteristics, Clinical Features, Diagnosis and Management

General Characteristics

The subtype H5 N1 influenza virus is a natural pathogen of chicken, ducks, turkeys and others. Though it was thought to be pathogenic only to them, the subtype H5N1 has crossed over to infect humans and caused small outbreaks. Hong Kong (1977) Thailand, Cambodia, Indonesia and several other Asian countries have reported outbreaks in poultry by H5N1 virus.

If human to human transmission of the virus becomes efficient, devastating pandemic more severe than the previous ones is likely to breakout. Pathologically the lesions resemble those of classic influenza, but hemophagocytic histiocytosis may also be seen.

Clinical Features

The incubation period for human influenza viruses is short-2 to 3 days (range 1-7 days). However with influenza A H5N1 the median time between exposure and onset of illness is 3 days (range 2 to 4 days). Most cases have occurred in previously healthy children and young adults. Symptoms of bird flu in humans include fever, cough, and sore throat, pneumonia, acute respiratory distress, and lifethreatening complications. The symptoms of bird flu may vary depending on the type of virus. Primary viral pneumonia and multi-organ failure are common. In the present outbreak, more than half of those infected with the virus have died. Death is due to respiratory failure and multi-organ failure especially respiratory, renal and cardiac failure.

Criteria for suspecting avian flu

Persons with illness characterized by fever, (temperature > 38oC), cough and/or sore throat, severe respiratory symptoms and one or more of the following:

1. Contact with a confirmed case of influenza A H5N1 during the infectious period,

2. Recent (less than 1 week) visit to a poultry farm in an area known to have outbreaks of HPAI (highly pathogenic avian influenza), or

3. Worked in a laboratory that is processing samples from persons or animals suspected to be having HPAI infection.

DIAGNOSIS

Procedure to Establish the Diagnosis

1. Suspect the disease and start investigations. Virus can be isolated from pharyngeal secretions 2-15 days after the onset of illness. Nasal secretions, blood, CSF and feces also contain the virus. Children may continue to shed the virus in nasal discharges for over 2 weeks after recovering from the acute attack.

2. Positive immunofluorescence antibody (IFA) using H5N1 monoclonal antibodies can be demonstrated in serum.

Diagnosis is confirmed by the following tests:

1. Positive viral culture for influenza A H5N1.

2. Positive real time PCR for influenza A H5N1.

3. and/or four-fold rise in H5N1-specific antibody titer.

MANAGEMENT

Avian influenza virus is resistant to amantadine and rimantadine. Oseltamivir 75 mg orally twice daily for 5 days and zanamivir would probably be useful if started as early as possible. No vaccine is available now to protect against H5N1 virus for general use.

A 2 dose regimen of 90 μg of sub-virion influenza A (H5N1) given IM over the deltoid muscle at 28 days interval generates neutralizing antibody. This vaccine is under trial.

Infection Control Precautions for Hospital Staff

Patients who have visited endemic regions within 10 days and who present with severe febrile illness and respiratory symptoms should be observed for avian influenza, with isolation, barrier nursing and other precautions.

1. Proper hand washing before and after contact with the patient.

2. Use gloves and gowns for all patient contacts. Use separate equipment for individual patients.

3. Protection of the eyes with goggles or face shields.

4. Precautions against droplet infection: Patients should be isolated in monitored negative air pressure ventilation systems. Health care staff should use a fittested respirator, or approved N-95 filtering mask when entering the room.

5. Suspected poultry meat and eggs should be properly cooked so that the whole item reaches a minimum temperature 70oC which is needed to destroy the virus.

ASPERGILLOSIS – General Characteristics and Treatment

General Characteristics

The species of aspergillus pathogenic to man are A. fumigatus, A. niger, A. flavus, A. terrens and A. nidulans. Of these A. fumigatus is most common. Infection occurs when general resistance is lowered or local disease favours superinfection. Aspergillus is very widespread in nature and their spores are found in dust. Both superficial and systemic lesions may develop. The commonest superficial lesion is otomycosis. Systemic infection may be pulmonary or disseminated. Major portal of entry is the respiratory tract.

Pulmonary form: Allergic alveolitis may develop due to inhalation of fungal spores in sensitized individuals. Aspergillus may grow in the bronchi to produce bronchopulmonary disease. The hyphae may obstruct the lumen. Healed tuberculous cavities or other types of cavities may be the seat of colonization by the fungus.

The mycelia grow to form a tangled fungal ball which is recognizable in X-rays (aspergilloma). It may remain asymptomatic or may cause massive hemoptysis. Invasive aspergillosis occurring in immunosuppressed individuals leads to widespread pulmonary necrosis with marked systemic symptoms.

Other sites of lesion are the central nervous system and naso-orbital cavities. Diagnosis can be made by histological demonstration of the fungus and isolation of the organism from the exudates. Since Aspergillus is a common contaminant in respiratory secretions, mere isolation does not prove its pathogenic role. Precipitating antibodies can be demonstrated by gel diffusion test and this test is of great value in diagnosis.

Treatment

Amphotericin B in a dose of 1 mg/kg/day is effective in systemic aspergilloma. Amphotericin B and 5-fluocytosine are effective in CNS disease. The underlying predisposing factor should be attended to. Cavities containing aspergilloma producing intractable hemoptysis have to be removed surgically. Other drugs like clotrimazole which are also effective in vitro are being evaluated. Other drugs effective against aspergillus include oral fluconazole itraconazole, voriconazole and posaconazole. Posaconazole can be given prophylactically against aspergillus and other fungal infections in neutrophilic patients. The dose is 200 mg tds oral. Capsofungin a new antifungal drug effective against aspergillus and other yeast species.

ASCORBIC ACID – SCURVY (ANTISCORBUTIC VITAMIN – VITAMIN C)

James Lind, a Scottish naval physician, recognized the antiscorbutic properties of citrus fruits in 1753 and this was considered an important discovery with far-reaching effects.

Dietary sources Ascorbic acid is present in a wide variety of foods. In the process of cooking about 50% of vitamin C passes into water and 20% gets destroyed. Fresh fruits, green leafy vegetables and germinating pulses are rich in ascorbic acid. The Indian gooseberry and guavas are particularly rich sources. Animal food like milk and meat contain only small amounts of this vitamin. The vitamin is present in potato in the layer just below the skin. If the potatoes are boiled whole with the skin, the vitamin diffuses into the deeper layers.

The minimum daily requirement for an adult is 30-40 mg and for infants 5 mg per kg body weight. Normal plasma levels vary between 0.7 and 1.5 mg per dL. Leukocytes, platelets, and adrenal glands contain large amounts of vitamin C. Deficiency of vitamin C causes scurvy.

Physiological actions

Vitamin C is a strong reducing agent. It takes part in biological oxidation-reduction reactions. Vitamin C is required for the formation of collagen by the hydroxylation of proline. It takes part in the formation of hemoglobin, erythrocyte maturation and the conversion of folic acid to tetrahydrofolate. Ascorbic acid reduces ferric iron to ferrous iron which is more easily absorbed. Body stores of ascorbic acid are small and, therefore, dietary deficiency leads to the development of scurvy.

SCURVY

Deficiency of vitamin C in the diet over a few weeks or months will lead to scurvy.

Clinical features of scurvy

Classic scurvy is seen only infrequently in India since small amounts of vitamin C are obtained in vegetables and pickled berries which form essential items of the Indian diet. Cases do occur among inmates of mental homes, elderly persons and among the very poor.

Manifestations of scurvy vary in children and adults. Early symptoms include weakness, lassitude, and normocytic normochromic anemia. In infancy and childhood subperiosteal hemorrhages occur, which lead to painful swellings over long bones. Scurvy in infancy produces pseudoparalysis owing to pain. This condition may mimic arthritis, osteomyelitis, or poliomyelitis. X-ray abnormalities may develop over the sternal ends of ribs and ends of long bones. Bleeding from the gums occurs commonly at the sites of erupted teeth.

Retrobulbar, subarachnoid, and cerebral bleeding may develop in a few cases. In adults early manifestation is follicular hyperkeratosis over the skin of the lower limbs. The lesions are papular with perifollicular hemorrhages which appear as purpura. Hemorrhage into the deep tissues of the thighs and legs cause tense induration (“woody leg”). Other sites of hemorrhage include joints, nail beds and viscera. The gums are hypertrophied and the interdental papillae are red and prominent (scurvy-buds). They bleed easily. Edentulous subjects do not get gingival abnormalities. The gum changes are aggravated by infection. The teeth become loose and may fall off. The hair assumes corkscrew shape since the follicles are obstructed by keratin plugs. Wound healing is delayed and resistance to infection is reduced. The condition is fatal if untreated.

Treatment

Scurvy is a potentially fatal disease and sudden death may occur unexpectedly. Treatment should be started without delay. In infants and children 25-50 mg of ascorbic acid given daily three times a day is sufficient to replete the body stores. In adults 500 mg is given daily in divided doses up to a total of 4 g. A diet rich in vitamin C should be given to prevent relapse.

Prevention

Infant foods should contain fruit juices or vitamin C supplements. Children, convalescent subjects and elderly people who are liable to be neglected, should receive 25 mg of vitamin C daily. As an alternative, 500 mg may be given once a month.

Adverse effects of vitamin C

Side effects like digestive upsets and hypoglycemia occur if the drug is given in doses exceeding 3 g/day. Oxaluria and oxalate stone formation in the urinary tract may result from prolonged overdosage.