AIDS (Acquired Immuno Deficiency Syndrome) – General Characteristics, Route of Transmission, Diagnosis, Clinical Features and Management

General Characteristics

AIDS is the name given to a group of disorders related to immunodeficiency produced as a result of the infection by the Human Immunodeficiecy Virus (HIV). The syndrome was first described in 1981 in LosAngeles in male homosexuals. In a short span of twenty four years, it has spread all across the globe, affecting various spheres of human life. AIDS is the final consequence of various changes that take place in the immune status of the individual and is characterized by the occurrence of opportunistic infections and specific malignancies.

The Causative Organism

The disease is caused by infection with HIV which is a retrovirus and belongs to the family of lentiviruses. Infections with lentiviruses typically show a chronic course of disease, a long period of clinical latency, persistent viral replication and involvement of the central nervous system. There are many viruses which are classified under this name. HIV-1 and HIV-2 are the major ones. Using electron microscopy, HIV-1 and HIV-2 are almost similar. However, they differ with regard to the molecular weight of their proteins, as well as having differences in their accessory genes. Both HIV-1 and HIV-2 replicate in CD4+ T cells and are regarded as pathogenic, HIV-2 being less pathogenic. HIV-1 is subdivided into groups: M (for main) and O (for outlier), antigenically. Within group M are the vast majority of HIV-1 strains subdivided into subtypes (currently 10: AJ) based on genetic variation. HIV-1 subtype B is more prevalent in homosexuals and IV drug users. However most of the ongoing HIV-1 epidemic around the world is due to non-B subtypes, especially subtype C in sub-Saharan Africa and India. But almost all subtypes have been identified in all parts of the world. HIV viruses are RNA viruses. HIV-1 viral particles have a diameter of 100 nm and are surrounded by a lipoprotein membrane.

During the process of budding, the virus may incorporate, different host proteins, such as HLA class I and II proteins, or adhesion proteins from the membrane of the host cell into its lipoprotein layer.

HIV has greatest affinity towards CD4 receptor bearing T helper lymphocyte group. Two newly identified proteins found on immune cells, CCR5 and fusin (also known as CXCR4) are considered as co-receptors. Certain chemokines are also considered important in modulating the entry of virus into the CD4 cell. After HIV successfully attaches and fuses with the cell, the RNA strands are transcribed to DNA by the timely activation of reverse transcriptase, a viral enzyme. The DNA strands thus formed in the cytoplasm migrate to the nucleus and integrate with the human DNA(with the help of enzyme integrase). This is an irreversible bonding and leads to the beginning of a permanent HIV infection.

The integrated human CD4 cell may take various routes. Some of them are detected by the person’s immune system and are eliminated promptly. Some of them get activated against other antigens or allergens and start producing chemical mediators. When parts of the DNA correspond to that of the virus, the proteins so produced will contain the amino acid sequences needed for the virus replication too. These ‘viral’ proteins are cleaved into correct sequence by the enzyme protease. The newly synthesized viral proteins acquire their coating from the CD4 cell surface and ‘bud out’ damaging the cell membrane. This leads to significant damage to the cells and they are destroyed in large numbers. Some of the cells undergo fusion and form syncitia. Some may be destroyed by cell mediated, complement mediated or antibody dependent cytotoxic mechanisms. Some CD4 cells undergo apoptosis (programmed and premature cell death). Thus the virus infection over a period of years leads to fall in the number of CD4 cells. The virus can also produce direct effects on cells in the brain, heart and bowel and reticulo endothelial system. HIV can replicate aggressively and upto 10 billion virus particles may be produced in a day with an average half life of 6 days.

The CD4 count in a normal person is between 800 and 1200 cells per cmm in peripheral blood. The CD4 cell is responsible for the smooth and coordinated function of all arms of the immune system. Once the CD4 function is compromised, various abnormalities occur. Both physiologic and dysregulated activation contribute to the profound immune activation and accelerated cell death that characterizes HIV infection. In early HIV infection, CD8+ T-cell numbers tend to increase, reflecting expansion of memory CD8+ T cells, particularly HIV reactive cells. CD8 cell expansion persists until far advanced stages of HIV disease, when all T-cell numbers tend to fall. A number of immunological abnormalities have been described including:

1. leukopenia and lymphopenia.

2. Loss of T4 lymphocytes from the peripheral blood.

3. hypergammaglobulinemia.

4. Skin anergy.

5. Decrease in lymphocyte proliferation, cytotoxic T cell response and antibody production to new antigens.

6. elevated levels of immune complexes, interferon and Beta 2 microgobulin

Immunodeficiency manifest in three different patterns:

a. reactivation of dormant infections like tuberculosis and herpes infections

b. infections by opportunistic pathogens

c. atypical manifestations of common infections.

The immune dysregulation also leads to development of specific malignancies such as Kaposi’s sarcoma related to HIV infection

Route of Transmission

HIV is susceptible to destruction by many physical and chemical agents. Close contact and exchange of blood or body fluids is necessary for transmission. The most rampant route is sexual intercourse. Male homosexuals practicing anal sex have the highest risk. Heterosexual anal sex, heterosexual vaginal sex, oral sex and sex using condoms have been stratified in the decreasing order of risk involved. The infection is common amongst IV drug users in whom sharing of contaminated needles, syringes and drugs is the risky factor. The infection can also be transmitted from the mother to the child during pregnancy, at the time of labor or during breast feeding. The transmission is most effective following transfusion of infected blood. Occasionally needles and sharps used in hospitals can act as sources of infection to health care professionals if proper precautions are not taken. HIV does not spread through casual contact, furniture, touching, sharing the food, utensils, toilet or through air or water.

Transmission by sexual intercourse is increased in the presence of other sexually transmitted diseases leading to ulcerative or inflammatory lesions in the genitalia. HIV infected mothers transmit the disease to their babies. Efficiency of transmission depends upon the viral load and clinical stage of the mother, the nature of delivery and time spent in labor. It can vary from 14 to 40%. The risk of transmission by accidental needle pricks in hospitals is around 0.3%.

DIAGNOSIS

HIV infection is a laboratory diagnosis and is made by demonstration of

i. HIV antibodies by ELISA or solid state card/spot tests

ii. Circulating antigens (p24) or

iii. The viral RNA itself by PCR –qualitative and quantitative- in peripheral blood.

Since false positive tests are not uncommon, it is advisable to repeat the tests using different types of ELISAs or different antigens before labelling an asymptomatic person as positive. If clinical symptoms have manifested two positive tests are considered enough.

Fallacies of the tests:

1. The test become positive only after the ‘window’ period i.e. 4-6 weeks or more after infection, by which time only the antibodies appear.

2. In the late stage when antibodies are too low, the tests may be only weakly positive or even negative.

Note: Testing for HIV should be done after counseling the patient and getting his permission.

AIDS is defined as the presence of one of the AIDS defining conditions or a decline of CD4 cells to less than 200 per cmm in an HIV infected person.

CLINICAL FEATURES

The spectrum of diseases caused by HIV is quite wide.

The clinical patterns are grouped into four stages.

• Acute Retroviral syndrome

• Asymptomatic stage

• Early symptomatic stage

• Advanced immunodeficiency

Acute retroviral syndrome (also called Primary HIV infection or seroconversion illness) occurs 2-6 weeks after the entry of HIV into human body. The illness is associated with fever, papular eruptions, arthralgia, lymph node swelling and oral ulcers

The CD4 count falls and viral load increases during this period. The symptomatic phase of acute HIV-1 infection lasts between 7 and 10 days, and rarely longer than 14 days. The severity and duration of symptoms have prognostic implications. Severe and prolonged symptoms are associated with more rapid disease progression, which may be unnoticed in the majority of cases. The infected person recovers completely to an asymptomatic stage with the return of CD4 count to normal but becomes IV antibody positive thereafter.

In the next few years many changes take place in the immune system even though the person is grossly asymptomatic. Immune mediated events like lymph node enlargement, thrombocytopenia, demyelinative disorders of central nervous system, occur with increasing frequency. Most of these are because of misdirected immunologic activity. The occurrence of persistent generalized lymphadenopathy (defined as enlargement of two or more extra inguinal lymph nodes of size 2-3 cm persisting for more than a month) is common at some time in this stage.

As the CD4 count drops to below 500 cells per cmm the person experiences reactivation of dormant organisms like tuberculosis (pulmonary and extra pulmonary), herpes zoster, disseminated herpes, molluscum contagiosum etc. Fungal infections of the genital tract, extensive non genital warts, exaggerated insect bite reactions on the exposed skin etc. are seen in this stage.

As the CD4 count drops below 200 cells per cmm, the opportunistic infections appear. This is also the time when neoplasms like high grade B cell lymphoma, Kaposi’s sarcoma, cervical intra-epithelial neoplasia and primary CNS lymphoma appear. Many infections which remain localized in immunocompetent subjects tend to become disseminated (e.g. M.tuberculosis, Toxoplasma gondii, Cytomegalovirus, Cryptococcus neoformans and Histoplasma capsulatum).

Respiratory System in AIDS

Respiratory system gets involved in almost all patients at some stage. The most important among these are Pneumocystis carinii Pneumonia (now re-named as P. jiroveci) and tuberculosis

Cutaneous Manifestations

Cutaneous manifestations these are quite common in AIDS. A broad spectrum of cutaneous infections caused by viruses, bacteria, fungi, protozoa, and parasites as well as many unusual manifestations of common dermatoses is seen.

Acute primary HIV infection may lead to a transient, generalized, morbilliform eruption on the trunk and the arms. With the person developing immunosuppression, nonspecific skin changes occur. These include common disorders with atypical clinical features, including recurrent varicella zoster, numerous hyperkeratotic warts, treatment-resistant seborrheic dermatitis, and oral hairy leukoplakia.

Chronic Herpes simplex virus (HSV) and Cytomeglovirus (CMV) infections, mycobacterial infections and mucocutaneous candidiasis occur in late stages.

Kaposi’s sarcoma (KS).

This was the first malignancy detected to be associated with HIV infection. The worldwide prevalence of KS in patients with AIDS may approach 34%. Most of the patients are homosexual men. KS is due to proliferation of endothelial cells induced by Human herpes virus type 8. KS begins as pink macules that become disseminated and palpable. Purplish or brown macules and plaques may become nodular. Mucosal involvement is common. The clinical progression of KS in patients infected with HIV is more aggressive than the other clinical types of KS.

Other malignancies can also occur more commonly with HIV infection. AIDS-related B-cell non-Hodgkin’s lymphomas may lead to skin nodules. Anal carcinoma and cervical intraepithelial neoplasia are papillomavirus associated tumours. These tumours tend to be more progressive and aggressive. An increase in squamous cell carcinoma of the anal mucosa has been reported, especially in young homosexual men. Intraoral or multiple squamous cell carcinoma, Bowen disease, and metastatic basal cell carcinoma have occasionally been reported.

Malignant melanoma occuring in patients with HIV is more aggressive than in individuals without HIV. Children with AIDS have a higher risk of developing leiomyosarcoma, although the incidence is still low in this population.

Fungal infections occur extensively on the skin and mucous membranes. Recurrent and persistent mucocutaneous candidiasis is common. Recurrent vaginal candidiasis can occur in any stage of the disease. In adults, generalized dermatophytosis, or tinea capitis, which is typically caused by Trichophyton rubrum is common. Onychomycosis in HIV infected may continue for many years.

Deep fungal infections like cryptococcosis, histoplasmosis and coccidioidomycosis may disseminate to the skin, usually as hemorrhagic papules or nodules.

Other infections: Mycobacterium tuberculosis; Mycobacterium avium-intracellulare complex; and, rarely, Mycobacterium kansasii may present as acneiform papules and indurated crusted plaques. Impetigo and folliculitis may be recurrent and persistent in HIV disease, particularly in children. Disseminated furunculosis, gingivitis, gangrenous stomatitis, and abscess formation can occur. Bacillary angiomatosis, which is caused by Bartonella henselae and rarely by Bartonella quintana, usually manifests as red papules and nodules. Atypical or Norwegian scabies, which is characterized by widespread hyperkeratotic, scaly maculopapular eruptions or crusted plaques, can occur. Seborrheic dermatitis like eruptions are observed in 83% of patients with AIDS. Seborrheic dermatitis may be the initial cutaneous manifestation of HIV disease. The eruption, which is characterized by widespread inflammatory and hyperkeratotic lesions, may progress to erythroderma in some patients. Pruritic papular eruption and eosinophilic folliculitis also presents with papular eruptions.

Nail and hair changes (graying and other pigmentary changes), photosensitive eruptions, and diffuse alopecia are noticed. Among sexually transmitted diseases, chancroid, syphilis in homosexual men, and lymphogranuloma venereum, are more commonly associated with AIDS. Syphilis coexisting with HIV creates special problems.

Treatment: Almost all cutaneous manifestations in HIV can be managed by the same modalities as in seronegative persons.

Neurological Manifestations

1. AIDS encephalopathy Infection of the CNS by HIV leads to encephalopathy (HIVE) which is also known by terms such as AIDS dementia complex, AIDS dementia, and HIV associated cognitive motor complex. HIVE is a late manifestation when there is a profound immune suppression with CD4 counts below 200 per cmm. HIVE is a subcortical dementia, caused by leukoencephalopathy typically emerging over the course of weeks and months. Typical complaints are slowing of reasoning, forgetfulness, difficulties concentrating, lack of energy and drive, mild depressive symptoms and emotional blunting.

Magnetic resonance imaging often shows patchy, diffuse, hyperintense and relatively symmetrical lesions in the white matter. These changes indicate leukoencephalopathy. HIV-associated myelopathy whose histopathological hallmarks are vacuoles, most prominent in the cervical and thoracic parts of the spinal cord, hence called vacuolar myelopathy

2. Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system predisposed to by AIDS. It is caused by JC virus (JCV), which is a polyoma virus found worldwide. The main focus of disease is the white matter of the cerebral hemispheres, but the cerebellum and in some cases the grey matter may also be affected. The median interval between the onset of the first symptoms and death was between 3 and 6 months. Patients usually die of secondary complications after being bedridden for many weeks. In addition to cognitive disorders, which may range from mild impairment of concentration to dementia, focal neurological deficits are very typical of PML.

Mono- and hemiparesis are observed most frequently, as well as defects of speech and vision. MRI usually shows asymmetrical high signal intensity lesions in T2-weighted imaging, hypointense in T1-weighted images. Usually they do not show gadolinium enhancement or mass effect. Non-involvement of the grey matter is characteristic. The lesions are almost always asymmetrical.

3. Cerebral toxoplasmosis almost always results from the reactivation of a latent infection with Toxoplasma gondii, Patients may present with seizure, headache or focal neurological deficits. Cerebral toxoplasmosis is extremely rare above a CD4 T cell count of 100/cmm. It should always be expected when the CD4 T cell counts fall below 100/cmm. A CT or MRI scan of the head should be performed promptly in all cases of focal neurological deficit. Ring enhancing lesions and solitary or multiple abcesses should suggest the infection. Up to 97 % of patients with cerebral toxoplasmosis have IgG antibodies, and therefore absence of these antibodies help to rule out toxoplasmosis.

4. Cryptococcal meningitis is more common in advanced immunodeficiency when the CD4 count is less than 200 cells per cmm. C. neoformans is transmited by droplet infection.

5. Primary CNS lymphomas are late complications of HIV infection, occurring in up to 10 % of AIDS patients. Almost all cases are EBV- associated. Neurological deficits occur depending on their location.

6. Peripheral neuropathy may complicate all stages of HIV infection. Acute inflammatory demyelinating polyneuropathy (AIDP) and Guillain-Barré syndrome (GBS) usually occur during seroconversion or during the latent stages of HIV infection. Chronic inflammatory demyelinating neuropathy, vasculitic neuropathy, distal symmetrical sensory polyneuropathy and drug induced neuropathies may occur are all reported.

7. Reactivation of CMV infection: When the CD4 count falls below 50/cmm reactivation of CMV infection can lead to retinitis. Any visual impairment occurring subacutely or acutely, such as blurred vision or floaters especially unilaterally should prompt immediate ophthalmological examination. Oral and/or intravitreal gancyclovir or valacyclovir will be useful if started early. Primary prophylaxis is not effective against CMV retinitis.

Cardiovascular System Involvement

Cardiovascular involvement is common in HIV-infected patients.

Pericardial diseases: Pericardial effusion, Pericarditis (viral, bacterial, fungal), neoplasms (Kaposi’s sarcoma, lymphoma).

Myocardial involvement: HIV-associated dilated cardiomyopathy, acute or chronic myocarditis, Kaposi’s sarcoma or lymphoma and adverse effects of antiretroviral drugs.

Endocardial involvement: Infective endocarditis—bacterial or fungal and nonbacterial thrombotic endocarditis

Vascular diseases: Arteriosclerosis, vasculitis, perivasculitis, pulmonary artery hypertension.

Other Miscellaneous Infections

Oroesophageal candidiasis: Candidias takes the form of extensive and persistent superficial lesions over the oropharynx, the buccal mucosa, tonsillar ring, tongue and the oesophagus. Candida esophagitis usually occurs with oropharyngeal involvement, but in about one third of the cases there may not be oral lesions. Esophagitis presents with odynophagia and retrosternal pain. Fluconazole therapy rapidly clears the infection.

MANAGEMENT OF HIV INFECTION

General measures: HIV infection should be confirmed beyond doubt by appropriate investigations. The immunological status is assessed by CD4 estimation. Severity of infection can be assessed by estimating the viral load using PCR test or other methods. The coexistence of opportunistic infections should be confirmed by investigations. Regular repetition of CD4 T-cell count and RNA viral load helps to assess the progress of the disease.

Antiretroviral therapy aims at bringing down the virus levels to undetectable levels, i.e. below 20 copies per ml with the presently available tests. This will ensure immune reconstitution with the return of CD4 counts above 200 per cmm. Symptom free survival is also prolonged.

Different groups of drugs are used. These include reverse transcriptase inhibitors, (RTIs) protease inhibitors (PIs) and entry inhibitors. The RTIs belong to two groups, the nucleotide and nucleoside RTIs (NtRTIs and NRTIs) and nonnucleoside RTIs (NNRTIs). The reverse transcriptase inhibitors block the transcription of DNA from viral RNA, without which the genetic material cannot be incorporated into the human DNA. The Protease inhibitors block the protease enzyme, effectively preventing the formation and release of new virions. The newly added class of fusion inhibitors blocks the virus fusion with the CD4 and other receptors on the cell membrane, thus preventing the entry of the virus into a new cell

PREVENTION

AIDS is though a dreaded disease is preventable too. Sex with a regular uninfected partner is the safest way to prevent HIV infection through sex. However condoms, if properly used offer almost complete protection against acquiring infection during natural sexual intercourse.

Strict screening of blood products for transfusion reduces the risk considerably. Transmission in parenteral drug abuse groups is tackled by supply of sterile syringes by governmental and other agencies. Other measures to reduce illicit use of habituating drugs include counselling, group therapy and legal measures to prevent drug trafficking. Transmission in hospital settings can be reduced by proper practice of universal (standard) precautions.

ATTENTION DEFICIT HYPERACTIVITY DISORDER – ADHD (HYPERKINETIC SYNDROME)

Attention Deficit Hyperactivity Disorder (ADHD)

This disorder is more common in boys. Persistent inattention, hyperactivity and impulsively are the cardinal features. These affect their scholastic performance.

Impulsive and reckless behavior is common. Brain damage due to birth trauma, allergy to food containing tartrazine, toxicity to lead and overactivity of peripheral adrenergic system are some of the recognized causes.

Treatment:

Stimulant drugs such as dexedrine 2.5-5 mg twice a day, clonidine, tricyclic antidepressants and monoamine oxidase inhibitors are beneficial. Many children become normal as they reach adolescence. Atomoxetine HCl is a recently introduced drug for this condition.

ACUTE POISONING – General Considerations, Clinical Presentation, General Management, Specific Measures, Forced Diuresis and Dialysis and Hemoperfusion

GENERAL CONSIDERATIONS

The high incidence of poisoning is attributed to the widespread use and free availability of insecticides, pesticides and other harmful chemicals for use in agriculture and industry. Depending upon the cost and local availability, varied substances are used. In the order of frequency, the toxic agents include organophosphorus compounds, barbiturates, benzodiazepines, vegetable poisons, phenothiazines, corrosive acids, and several others. The precipitating factors, which drive persons to commit suicide, are depressive illness, financial problems, domestic conflicts, and frustration in studies and jobs or incurable illness. Among epileptics and alcoholics the incidence of suicidal poisoning is high. Accidental poisoning is common in children. Persons engaged in the use of toxic chemicals in agriculture and in industry are liable to suffer if proper safety precautions are not adhered to.

CLINICAL PRESENTATION

Though poisoning by many chemicals lead to characteristic clinical features, in the majority of cases symptoms are non-specific and may be mistaken for other acute illnesses. The common presentations are coma, acute psychosis, convulsions, gastroenteritis, circulatory collapse, or pulmonary edema.

Corrosive poisons produce noticeable lesions at the points of maximum contact such as the mouth, esophagus and stomach. Other poisons affect specific organs maximally, e.g. liver damage in paracetamol poisoning, renal damage in copper sulphate poisoning, and cardiac dysfunction in Cerebera odollam poisoning. Poisons consumed on an empty stomach are absorbed more rapidly than if taken on full stomach. Also, if taken along with alcohol, many poisons are quickly absorbed and their damaging effects are cumulative.

Diagnosis

Diagnosis is rendered easy if proper history or evidence of the material is obtained, but in many cases such help is not available. A high index of suspicion on the part of the physician is absolutely necessary for arriving at an early diagnosis in such cases. Abrupt occurrence of acute illness in a person who is in good health should suggest acute poisoning as a possibility. Smell of alcohol or kerosene, severe respiratory depression, circulatory collapse, convulsions, constricted pupils, cardiac arrhythmias, dystonic postures, and muscle fasciculations add support to this diagnosis.

The outcome depends upon factors like:

1. The amount of poison and its mode of administration,

2. Presence of food in the stomach at the time of ingestion,

3. Delay in starting treatment,

4. Age,

5. General health and concurrent illness, and

6. Availability of specific antidotes.

Patients who are comatose due to acute poisoning face the twin dangers of the toxic-effects of the chemical and the grave consequences of an obstructed airway.

GENERAL MANAGEMENT

Acute poisoning is a medical emergency and is best treated in a well-equipped hospital with teams specially trained to handle such cases. Since in many cases the nature of the poison will not be evident at first, the aim of treatment is to keep the patient alive with support of vital functions, eliminate as much of the poison as possible from the body and prevent further absorption of poison. Specific antidotes are given as soon as the nature of the poison is known. Selective antidotes are available only for 2% of such poisons.

Emergency Management

Most important is to clear the airway and ensure adequate ventilation by positioning, suction, or by insertion of nasal or oropharyngeal airway. The respiration should be clinically assessed and if there is ventilatory impairment necessary support with supplemental oxygenation and mechanical ventilation should be instituted. Intermittent positive pressure respiration has to be started with endotracheal intubation, if conservative measures fail. The patient should be turned from side to side at four-hourly intervals to prevent aspiration and hypostatic pneumonia. Frequent bronchial suction helps to prevent atelectasis and aspiration pneumonia.

Shock is managed on the usual lines. Maintenance of fluid and electrolyte balance is of utmost importance in all cases.

Decontamination of skin

Pesticides and other chemicals which are present on the cloths and skin get absorbed through the skin and worsen the condition. Similarly corrosive agents rapidly injure the skin and eyes. In these situations washing the affected area with large quantities of water and soap prevents further systemic absorption of the toxin. Normal saline is preferred for irrigation of the eyes.

General Measures

An intake output chart should be maintained and a urine output of at least 1500 mL should be ensured. Replacement of electrolytes and correction of acidosis should be done with proper laboratory monitoring. Maintenance of nutrition is equally important. Diet containing 2000 calories should be given orally if the patient is conscious. In unconscious patients food has to be given through a nasogastric tube. Parenteral nutrition has to be started in severely affected patients.

Repeated examination of blood and urine for the level of the toxic agent helps to monitor the progress with treatment.

Specific Measures

a. Ingested poisons

In many cases of ingested poisons, considerable amounts remain in the gastrointestinal tract up to four hours; hence it is absolutely necessary to take appropriate measures for their removal. Induction of vomiting is safe in conscious patients. Vomiting is induced by tickling the pharynx or administration of gastric irritants such as concentrated common salt solution 200-400 mL. In the case of corrosive poisons and highly irritant substances like kerosene, emesis and gastric intubation are contraindicated. Gastric lavage by using a stomach tube is an effective method to empty gastric contents rapidly and this can be done even in unwilling patients. This is the method of choice in all conscious patients who have consumed noncorrosive poisons. However, it is risky in comatose patients due to the danger of aspiration into the respiratory tract and in such cases aspiration through Ryle’s tube is preferable. Gastric contents should be preserved in a sealed bottle for chemical examination and further medicolegal procedures. Use of activated charcoal, which adsorbs many toxins reduces gastric and intestinal absorption further. Dose is 50-200 g in 200 mL water initially and 50 g 6 hourly till recovery. The surface area of activated charcoal is increased several folds, compared to the parent substance and this large surface area adsorbs several substances non-specifically.

Purgatives such as magsulph. 15-30 g or sorbitol 1 g/kg bw (maximum of 150 g) orally followed by bowel wash 2 hours later help to eliminate the poison from the intestine.

b. Removal of absorbed poisons

Forced diuresis enhances the renal excretion of many poisons. Hemodialysis helps to eliminate many water soluble substances.

Forced Diuresis

The kidneys can be made to eliminate poisonous drugs at a rate consistent with the urine output. Contraindications include congestive cardiac failure, renal failure, rhabdomyolysis and cerebral edema. In an unconscious patient a Foley’s catheter should be introduced to facilitate uninterrupted flow of urine and for proper monitoring of output.

Dialysis and Hemoperfusion

Dialysis

Since most of the cases recover with forced diuresis, hemodialysis is indicated only in a few. Indications for hemodialysis are: (a) high blood levels of the drug, (b) renal failure, and (c) non-responsiveness to forced diuresis and (d) poisoning associated with deep coma, hypotension and fluid and electrolyte disturbances. In the absence of facilities for hemodialysis, peritoneal dialysis should be undertaken. Hemodialysis is 6-10 times more efficient than peritoneal dialysis.

Hemoperfusion is the process of passing the patient’s blood through cartridges packed with activated charcoal, which adsorbs drugs and toxins such as barbiturates, carbamazepine, glutethimide, meprobamate, methaqualone and several others.

Multiple dose activated charcoal Doses of activated charcoal 1-2g/kg bw repeated every 2-4 hours hasten elimination of drugs by adsorption of drugs excreted into the gut lumen (gut dialysis).

Antidotes

Antidotes are available for 2% of the poisonous substances. These may be chemical antidotes, which neutralize the action of the poison, or biological antidotes, which prevent their pharmacological response. They should be employed only after ascertaining the nature of the poison. In most cases, the antidote is indicated by the manufacturers on the packing of the toxic chemical

Many of the patients with suicidal poisoning attempt to repeat these episodes because of their psychiatric problems. Hence, it is necessary to instruct their relatives and also arrange for proper psychiatric treatment after the initial episode is treated.

FORCED DIURESIS

This is employed when the toxin is removable by the kidney and the metabolites are toxic to the system. A substantial proportion of the poison is excreted in the urine unchanged. The poison should be distributed mainly in the extracellular fluid and only minimally bound or not bound at all to proteins.

Rationale

Elimination of the toxic substance is enhanced by manipulation of the urine pH so as to render the toxin in the ionized form. Forced diuresis should be considered, and may be indicated, in poisoning due to the following substances.

Potential complications

1. Fluid overload

2. Pulmonary edema

3. Cerebral edema

4. Electrolyte and acid-base disturbances.

Diuresis is induced by giving 5% glucose continuously IV as drip and frusemide IV in dose of 20 mg 6th hourly depending on the response. Proper estimation of electrolytes and acid-base states should be undertaken during and after the procedure.

Forced acid diuresis

The urine pH is adjusted to 5.5-6.5 by giving: 10 g arginine or lysine hydrochloride intravenously over 30 minutes followed by ammonium chloride 4 g 2 hourly, by mouth.

Forced alkaline diuresis

The urine pH is adjusted to 7.5-8.5 by giving boluses of 50 mmol (approx 50 mL) of 7.5% sodium bicarbonate solution. Often 200-300 mmol is required in the first 1-2 hours. Since a large sodium load is being given with the bicarbonate cardiac failure may be precipitated in susceptible individuals.

DIALYSIS AND HEMOPERFUSION

In hemodialysis, materials, which are dialyzable including toxic materials, are dialyzed across a semipermeable membrane, using appropriate solutions, which will permit the removal of the toxic substance. Dialysis machines are available in several hospitals offering secondary care.

Hemoperfusion is the removal of the toxic material by perfusion of blood through a cartridge containing material, which will absorb the particular substance.

Requisites for Instituting Dialysis Procedures

1. The drug or toxic substance should diffuse easily through the peritoneum or dialysis membrane or be readily adsorbed to activated charcoal or uncharged resin.

2. A significant proportion of the poison should be present in plasma water or be capable of rapid equilibration with it.

3. The pharmacological effect of the substance should be directly related to the blood concentration.

4. Antidote is not easily available.

Depending on the situation any one of the procedures can be adopted. Compared to peritoneal dialysis, the other procedures are thrice more efficient.

Indications for Dialysis and Hemoperfusion

1. Severe clinical intoxication as shown by grade IV coma, hypotension, hypothermia and hypoventilation caused by hypnotic drugs

2. Progressive clinical deterioration, despite adequate supportive management.

3. High plasma concentration of the toxic agents. Drugs that can be effectively dialysed includes barbiturates, phenytoin, primidone, paraldehyde, chloral hydrate, amphetamine, alcohols, methanol, ethylene glycol, salicylates, paracetamol, several antibiotics, isoniazid, quinine, quinidine, metallic salts including lithium, bromide, iodide and potassium, ergotamine, carbon tetrachloride toxic principles of mushrooms and others.

Contraindications

1. The toxic substance is a rapid acting metabolic poison.

2. The effect of the substance is irreversible, e.g. organophosphorus compounds.

3. The drug is relatively non-toxic, e.g. benzodiazepines.

4. The drug has a very large volume of distribution.

5. Cardiogenic shock.

6. Coagulopathy.

Potential Complications

1. Thrombocytopenia (about 30% reduction)

2. Leucopenia (about 10% reduction)

3. Loss of clotting factors.

4. Lowering of calcium, glucose

5. Bleeding tendency due to heparinization

6. Patient may disconnect shunt lines

7. Air embolism

8. Infection

The choice of elimination technique should depend upon the plasma level of the substance.

INFECTION – GENERAL INFORMATION (Types, Sources and Pathogenesis), PATHOGENESIS, APPROACH TO PATIENT WITH FEVER, SYSTEMIC RESPONSES AND LAB INVESTIGATIONS

INTRODUCTION

Microbes are abundant in nature, the vast majority of them harmless to man and many of them essential to life. They are mostly commensals and a few are pathogens. The organisms capable of establishing themselves and multiplying in hosts are called parasites, which may be commensals or pathogens. All our body surfaces have an indigenous bacterial flora. This normal flora protects us from infection by multiple mechanisms 1, compete with pathogens in utilizing nutrients. 2, producing antibacterial substances inhibiting growth of pathogens. 3, inducing host immunity that is cross reactive and effective against pathogens.

Pathogens lead to adverse effects on hosts while commensals cause no harm to their hosts and exist in harmony. Commensals may cause disease when host resistance is lost or when transferred to an inappropriate site, e.g. oropharyngeal commensals aspirated into lung.

Infection:

Infection is defined as multiplication of microbes in the tissues of the host with or without producing disease. Infections without disease manifestations are called subclinical infections.

Infections remain one of the main causes of morbidity and mortality in man worldwide. Poverty and overcrowding in the underdeveloped countries increase this burden. Infectious agents include bacteria, viruses, fungi, protozoa, helminths and prions.

Types of Infections

1. Exogenous infections: Infection from external source.

2. Endogenous infection: Infection by organisms harbored by the individual.

3. Primary infection: Initial infection of a host by an organism.

4. Secondary infection: Host suffering from an infectious disease invaded by another organism.

5. Re-infection: Subsequent infection by same organism.

6. Focal infection: Infections confined to one area/organ e.g. Tonsillitis.

7. Nosocomial infection: Infection acquired after admission to hospital.

8. Super infection: Patient receiving broad spectrum antibiotics get colonized by resistant pathogens and infection produced by them.

9. Opportunistic infection: Organisms that ordinarily do not cause infection in healthy individuals but do so in individuals with markedly reduced resistance (Immunocompromised hosts).

10. Latent infection: Pathogen remains in the tissue without producing disease but may lead to disease when host resistance is lowered.

Source of infection:

Infection may be obtained from human, animal or other sources. When the source of infection is man, the infectious agent may originate from patients or carriers.

A carrier who harbours the pathogenic organism without developing any disease due to it, is called healthy carrier.

A convalescent carrier is one who harbours the organism for some period after recovering from the disease.

Zoonoses are infections transmitted from wild or domestic animals to man e.g. plague, rabies.

Some infections are transmitted by insect vectors e.g. Anopheles mosquito transmits malaria.

Direct contact is necessary for transmission of organism like Staphylococci. Respiratory diseases such as influenza, tuberculosis, pneumonia and others spread by air-borne droplets. Food or Water borne transmission occurs in typhoid, hepatitis A and E, cholera and others. Sexual transmission is the main route for syphilis, gonorrhea and HIV. Vertical transmission i.e. from mother to fetus occurs in diseases like rubella and syphilis.

PATHOGENESIS

The pathological lesions, symptoms and signs may be produced by several mechanisms:

1. Caused by the organism directly e.g. Boils, abscesses, pneumonia, dysentery, tuberculosis.

2. Organisms like C. diphtheriae and Cl. tetani multiply locally without entering the system and elaborate toxins (exotoxins) which are absorbed into the system producing the manifestations.

3. Vibrio cholerae elaborates an exotoxin having local effect on the intestinal mucosa producing secretory diarrhea.

4. Many gram negative bacteria produce endotoxins by disintegration in the tissues producing direct effect on tissues and liberation of chemical mediators of inflammation like cytokines which are mainly responsible for the manifestations.

5. Activation of immunological mechanism is one of the most important pathogenic mechanisms of tissue damage in several infections.

6. Infections like HIV and syphilis suppress the immune mechanism of the host by acting upon the lymphocytes.

7. Some infectious agents are oncogenic i.e. giving rise to tumours- e.g. HIV, EB virus, hepatitis B and others. Medical care itself increases the patient’s risk of acquiring infection in several ways:

1. Contact with pathogens in the hospital.

2. Breach of skin (e.g. incisions, IV devices) or mucous membranes (e.g. endotracheal tube, indwelling catheter).

3. Alteration of normal flora by antibiotics.

4. Reduction of immunity by immunosuppressive drugs.

The body’s mechanisms to prevent and overcome the infections are local defenses, phagocytic cells, antibodies (immunoglobulins), immunocytes and nonspecific defense aids such as lysozymes, complement and properdin.

Changing scenario of infection worldwide: The pattern of infectious agents and pathogenesis are changing due to seceral factors such as changes in environment, influence of polymicrobial therapy and alterations in host defences.

Newly recognized infections are AIDS, severe acute respiratory distress syndrome (SARS), avian influenza and others.

Rebound of diseases like, malaria, tuberculosis, rheumatic fever and others thought to have been eradicated from developed countries. Recognition of role of infectious agents in the causation of diseases previously thought to be non-infectious e.g. Helicobacter pylori in the causation of peptic ulcer, Human papilloma virus in carcinoma cervix.

Human Polymicrobial Infections

In the immunocompetent state, colonization by one organism inhibits colonization by another. This is known as microbial interference e.g. S. pneumonia and S. aureus. At present, due to the prevalence of different kinds of immunosuppressed states, polymicrobial disease caused by combination of viruses, bacteria, fungi and parasites are being recognized. In this situation, presence of one micro-organism causes a niche for the other pathogen to colonize and thrive e.g. measles, tuberculosis and S.aureus; EB virus and retrovirus; HBV and HIV; HIV and tuberculosis.

Immunodeficiency states may be congenital or acquired. The latter include malnutrition, extremes of age, loss of surface epithelium, diabetes mellitus, cancer, cancer chemotherapy, chronic renal failure, chronic hepatic failure, immunosuppressant drugs, HIV infection and others. The resultant degree of immune suppression is the total effect of all the contributory factors. Immunodeficiency may be general or specific towards specific pathogens. Neutropenia and reduction of other phagocyte cells predispose to infection by extra cellular bacterial pathogens, both endogenous and exogenous. Suppression of T-cell mediated immunity predisposes to viral infections. Multiple intubations, hospitalization and management in intensive care facilities predispose to infections.

Clinical features of infection in the immunocompromised host differ from those in immunocompetent hosts. Signs of infection in the immunocompromised hosts include:

1. confusion

2. faint erythematous rashes

3. lymphangiectatic streaks on the skin

4. pleurisy dyspnoea or cough with clear chest X-ray

5. minimal erythema with serosanguineous discharge at sites of insertion of catheters, surgical sites, abscess or drains

6. minimally elevated values of liver function tests, and serum levels of LDH (lactic dehydrogenase) and C K (Creatine kinase) and

7. unexplained rise or fall of leukocytes and platelet counts.

Antimicrobial resistance:

As we developed newer antimicrobial drugs, microbes developed the ability to elude our best weapon. Antibiotic resistance is developing at an alarming rate. Multidrug resistant pathogens such as E. coli, Klebsiella, Pseudomonas, Staph. aureus, M.tuberculosis, HIV, and others are extremely common. Especially in the ICUs these get disseminated.

Bioterorrism:

Use of biological infectious agents such as anthrax spores, plague, small pox and others may be resorted to as potential weapons for stealthy warfare. Eradication of infectious diseases like smallpox totally from the world and polio from most countries has been achieved.

PATHOGENESIS OF FEVER

PATHOGENESIS

Pyrogens are substances causing fever. These may be exogenous or endogenous. Exogenous pyrogens are molecules which interact with host cells to induce secretion of pyrogenic cytokines. Most of these are microbial products, microbial toxins or whole microorganisms.

The best example is the lipopolysaccharide endotoxin found in the cell wall of gram-negative bacteria. Enterotoxin of S. aureus and Group A and B streptococci are other examples. Endogenous pyrogens are cytokines which are small molecular weight proteins most important being interleukin.1 (IL-1), IL-2 and tumour necrosis factor alpha (TNF α). The synthesis and release of pyrogenic cytokines are induced by a wide spectrum of exogenous pyrogens most of which are of bacterial, fungal or viral origin. In addition, inflammation, trauma, tissue necrosis and antigen–antibody complexes induce production of pyrogenic cytokines. Main source of pyrogenic cytokines are monocytes and macrophages, and to a lesser extent neutrophils and lymphocytes.

Pyrogenic cytokines stimulate production of the prostaglandin – PGE2 from arachidonic acid near the hypothalamic thermoregulatory centre. Arachidonic acid is released from cell membrane by the enzyme –Phospholipase A2. PGE2 raises the set point in the thermoregulatory center. Pyrogenic cytokines also induce production of PGE2 in the periphery which is responsible for myalgia, arthralgia and malaise that accompany fever.

Fever as a Defense Adaptation

There is suggestive evidence that, for some microorganisms at least, a febrile host response may assist in curtailing infection and speedy recovery. Experimental data support the notion that raised body temperature interferes with growth and / or virulence factors of some bacterial and viral pathogens. Fever, slightly increases immune reaction and increases chemotactic, phagocytic and bactericidal activity of polymorphonuclear leukocytes.

In immunocompromised individuals and those at the extremes of age, a prompt febrile response may notdevelop even in the presence of severe infection. Such persons are at greater risk of succumbing to the infection.

INFECTION – APPROACH TO PATIENT WITH FEVER

APPROACH TO PATIENT WITH FEVER

In the diagnosis of the cause of fever, science and art of Medicine come together. History is most important.

History of travel to a malaria – endemic area may give a clue. Presence of nasal symptoms and sore throat suggest viral etiology. Severe myalgia may suggest Influenza, Dengue fever or Leptospirosis. Eye congestion, subconjunctival hemorrhage and muscle tenderness may suggest leptospirosis. Skin rashes and mucous membrane lesions give diagnostic clue. Erythematous blanching rash indicates viral exanthematous fever as the most likely cause. Palatal petechiae along with posterior cervical lymphadenopathy and grey white tonsillar exudates suggests infectious mononucleosis. Enlarged tender tonsillar lymph nodes with tonsillar exudate and neutrophilic leukocytosis suggest streptococcal tonsillitis. Koplik’s spots in the buccal mucosa indicate measles. Dysuria and loin pain with tenderness suggests pyelonephritis.

Duration of Fever: This is an important point which helps in clinical diagnosis. Regular recording of temperature, pulse rate and respiration rate are routinely done in all hospitals. Fever of more than 5 to 7 days with gastro intestinal symptoms with or without malena and just palpable soft spleen may suggest typhoid fever. Onset may be abrupt in infections like pneumonia or may show a step-ladder type of rise in typhoid. Fever with clubbing of fingers and splinter hemorrhages in the nail bed in a patient with congenital or rheumatic valvular heart disease should suggest infective endocarditis.

Patterns of Fever: Recording the pattern of temperature is an important clinical clue to diagnosis. In the ordinary febrile patient, temperature is recorded thrice daily, but in special cases where large fluctuations occur and in acute care settings temperature has to be recorded more frequently.

Continuous Fever Temperature is persistently elevated with diurnal variation of less than 1^oC e.g. Typhoid in the 2nd week, typhus, viral infections and others.

Remittent Fever – Temperature is persistently elevated with diurnal variation more than 1^oC – typhoid in 1^st week, brucellosis, leptospirosis and others.

Intermittent Fever – Temperature is discontinuous, touching normal at least once in 24 hours. This may be seen in pyogenic infections,  lymphomas, tuberculosis, bacteremias, malaria and others.

Periodic Fever: These show a regular periodicity in their occurrence. Fever occurring on alternate days with one day interval in between is called tertian periodicity e.g. vivax malaria (benign tertian). Fever occurring every 4^th day with 2 days’ afebrile period in between is known as quartan periodicity e.g. quartan malaria. Continuous and remittent fevers may be converted to intermittent fever by repeated doses of antipyretics.

Drug Induced Fever Several drugs can produce fever by various mechanisms. These include allergy, systemic metabolic effects and agranulocytosis. Drug induced fever becomes a diagnostic problem in patients receiving multiple drugs for long periods, especially in hospitals.

Of the medications that cause fever, antibiotics are the most frequent–especially penicillins and cephalosporins, sulfonamides, nitrofurantoin, antituberculosis agents and others. Antiepileptic drugs especially phenytoin are also known to cause fever. Drug induced fever does not have specific characteristic features. Most often, it occurs 5 to 10 days after starting the drug, but can occur even after the first dose itself.

INFECTION – SYSTEMIC RESPONSES IN FEVER

SYSTEMIC RESPONSES IN FEVER

• Increase in metabolic rate – Oxygen consumption increases by 13% for each 1^oC rise of temperature. Hence fever may aggravate or precipitate pre-existing cardiac, cerebrovascular or pulmonary insufficiency.

• Increase in heart rate. For every 1^oC rise of temperature above normal, the heart rate increases by 18/minute. In some fevers like pneumonia and rheumatic fever, heart rate may be disproportionately high (rapid pulse fever). In typhoid, some viral infections, meningitis, brucellosis, drug induced fever and many cases of leptospirosis; pulse rate may be disproportionately slow (slow pulse fever).

• Blood pressure may increase during the period of rise of temperature because of vasoconstriction and decrease during the period of defervescence because of vasodilation.

• Fluid loss increases due to evaporation and sweating–average of 360 mL excess fluid is required for 24 hours for 1^oC rise in temperature.

• Increase in respiratory rate occurs with fever. The usual ratio of 1:4 with heart rate is maintained except in the case of primary respiratory diseases such as pneumonia and pleural effusion.

• Chills occur in the initial phase because of peripheral vasoconstriction.

• Rigors accompany rapid increase in temperature. They are due to vigorous muscle contractions. Repeated occurrence of rigor is most typically seen in malaria, filariasis, urinary tract Infections, and abscess formation anywhere in the body. Rigor may occur in many types of continuous fever treated intermittently with antipyretics. When the effect of the drug wanes off rigor occurs in an attempt on the part of the body to resume the high temperature.

• When the high temperature falls to normal or subnormal within a few hours, it is called Fall by Crisis, and when the temperature reaches normal slowly over several days, it is called Fall by Lysis.

• Headache may accompany any type of fever but severe headache and photophobia are characteristic prominent features of intracranial infections and sinusitis.

• Delirium – This is toxic confusional state. It is more common in the very young and very old. Fever may induce mental changes in those with organic brain syndrome. The cytokines TNFα and IL-1 cause release of endorphins in the brain and may precipitate delirium.

• Excessive sweating is the regular accompaniment of defervescence. Particular patterns of sweating like “night sweats” are characteristic of tuberculosis and lymphoma. In almost all fevers fall of temperature is accompanied by sweating.

• Muscle pain – (myalgia) is characteristic of infections such as influenza, enterovirus, dengue fever, leptospirosis and others.

• Herpes labialis – Fever may activate the latent viral infection Herpes simplex which causes vesicles at muco-cutaneous junctions of the nose and lips. Pneumonia and meningitis are common to produce Herpes labialis whereas typhoid is very rare to do so.

• Feverishness: This is a subjective feeling of fever which may be experienced even without rise in temperature. Feverishness has not got the same pathological importance of fever. Therefore it is essential to record the temperature to distinguish between the two conditions.

INFECTION – FEVER OR INFECTION DETECTION – LAB INVESTIGATIONS

FEVER OR INFECTION DETECTION – LAB INVESTIGATIONS

Leukocyte Patterns

Neutrophil Leukocytosis and presence of juvenile or band forms of neutrophils and toxic granulations in neutrophils usually suggest bacterial infections. The severity of leukocytosis may also indicate the severity of sepsis. Total leukocyte counts above 10,000/cmm with more than 70% as neutrophils are very suggestive of pyogenic infection. Leukemoid reaction may accompany severe leukocytosis.

Neutropenia, mild to moderate, is usually seen in many viral infections, about 25%, of typhoid, brucellosis, leishmaniasis, tuberculosis, histoplasmosis and others.

Leukopenia with relative or absolute lymphocytosis occurs in several viral infections. Many viral infections show moderate or even severe thrombocytopenia with or without bleeding manifestations.

Atypical lymphocytes – are seen in some viral infections especially Epstein–Barr virus, cytomegalo virus, HIV, dengue, rubella, viral hepatitis, varicella and others.      

Monocytosis is commonly seen in typhoid and tuberculosis.

Eosinophilia: Occurs in parasitic infections, filariasis, tropical pulmonary eosinophila and hypersensitivity to drugs.

1. Isolation or identification of the infective agent in blood/urine/body fluids/pus and tissues specimens

a. Culture: Proper collection of sample without contamination and transport to the lab is important e.g. blood culture in sepsis, urine culture in UTI, CSF in meningitis, sputum in pneumonia, pus in abscess.

b. Gram stain of specimen may help e.g. sputum, CSF, pus, urethral discharge and others. The findings on gram stain should correspond to the results of culture, to be diagnostic.

c. Demonstration of parasites like malaria and microfilaria in blood, leishmania in bone marrow and liver biopsy specimens, vegetative amoeba in stool or scrapings from abscess wall.

2. Demonstration of antibodies to specific pathogen e.g. Widal in typhoid, IgM antibodies against many viruses like hepatitis A, E and dengue virus.

3. Detection of bacterial/fungal/viral antigens in blood/body fluids even when cultures are negative or practically difficult e.g. HBsAg in virus B hepatitis.

4. Detection of very minute quantities of foreign nucleic acid by techniques such as PCR (polymerase chain reaction) that allow amplification of specific DNA/RNA sequences.

5. Histopathology: e.g. tuberculosis, histoplasmosis, sarcoidosis and others can be diagnosed by biopsy of lymph node, liver and other organs.