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Presentators Day, Date Supervisor

: Halimatusakdiah, Daniel Rajkumar : Tuesday, August 27th,2013 : dr.Supriatmo, SpA (K) CHAPTER 1 INTRODUCTION

1.1.

Background

Tuberculosis (TB) is contagious and airborne. It is a disease of poverty affecting mostly young adults in their most productive years. The vast majority of TB deaths are in the developing world- 1.7 million people died from TB (including 380 000 women) in 2009, including 380 000 people with HIV, equal to 4700 deaths a day. The TB death rate has fallen by 35% since 1990, and the number of deaths is also declining TB is among the three greatest causes of death among women aged 15-44. There were 9.4 million new TB cases (including 3.3 million women) in 2009, including 1.1 million cases among people with HIV . The estimated global incidence rate fell to 137 cases per 100 000 population in 2009, after peaking in 2004 at 142 cases per 100 000. The rate is still falling but too slowly. Globally, the percentage of people successfully treated reached the highest level at 86% in 2008. Since 1995, 41 million people have been successfully treated and up to 6 million lives saved through DOTS and the Stop TB Strategy. 5.8 million TB cases were notified through DOTS programmes in 2009. Of the 22 TB high burden countries, 13 countries are on track to meet the 2015 Millennium Development Goal target and 12 countries are on track to reach the 2015 Stop TB Partnership targets. 1.6 million TB patients knew their HIV status in 2009 compared to 1.4 million in 2008 with the highest HIV testing rates of TB patients in Europe (86%) Africa (53%) and the Americas (41%). In 55 countries, including 16 in Africa, at least 75% of TB patients knew their HIV status. 37% of HIV-positive TB patients were enrolled on antiretrovirals and 75% started on cotrimoxazole preventive treatment in 2009. Multidrug-resistant TB (MDR-TB) is a form of TB that is difficult and expensive to treat and fails to respond to standard first-line drug. There were an

estimated 440 000 new MDR-TB cases in 2008, and 150 000 deaths from MDRTB. It was estimated that in 2009, 3.3% of all new TB cases had MDR-TB. In 2010, the largest WHO MDR-TB survey reported the highest rates ever of MDRTB, with peaks of up to 28% of new TB cases in some settings of the former Soviet Union. - Many countries have developed plans to address MDR-TB, but the response globally is still insufficient. Extensively drug-resistant TB (XDRTB) occurs when resistance to second-line drugs develops on top of MDR-TB. XDR-TB cases have been confirmed in 58 countries. The World Health Organization (WHO) defines malnutrition as "the cellular imbalance between the supply of nutrients and energy and the body's demand for them to ensure growth, maintenance, and specific functions." The term protein-energy malnutrition (PEM) applies to a group of related disorders that include marasmus, kwashiorkor, and intermediate states of marasmuskwashiorkor. The term marasmus is derived from the Greek word marasmos, which means withering or wasting. Marasmus involves inadequate intake of protein and calories and is characterized by emaciation. The term kwashiorkor is taken from the Ga language of Ghana and means "the sickness of the weaning." Williams first used the term in 1933, and it refers to an inadequate protein intake with reasonable caloric (energy) intake. Edema is characteristic of kwashiorkor but is absent in marasmus. Studies suggest that marasmus represents an adaptive response to starvation, whereas kwashiorkor represents a maladaptive response to starvation. Children may present with a mixed picture of marasmus and kwashiorkor, and children may present with milder forms of malnutrition. For this reason, Jelliffe suggested the term protein-calorie (energy) malnutrition to include both entities. Although protein-energy malnutrition affects virtually every organ system, this article primarily focuses on its cutaneous manifestations. Patients with protein-energy malnutrition may also have deficiencies of vitamins, essential fatty acids, and trace elements, all of which may contribute to their dermatosis

CHAPTER 2 LITERATURE REVIEW 2.1. TUBERCULOSIS 2.1.1 Definition TB is an airborne disease caused by the bacterium Mycobacterium tuberculosis (M. tuberculosis) . M. tuberculosis and seven very closely related mycobacterial species (M. bovis, M. africanum, M. microti, M. caprae, M. pinnipedii, M. canetti and M. mungi) together comprise what is known as the M. tuberculosis complex. Most, but not all, of these species have been found to cause disease in humans. 2.1.2. Etiology TB is caused by M tuberculosis, a slow-growing obligate aerobe and a facultative intracellular parasite. The organism grows in parallel groups called cords (as seen in the image below). It retains many stains after decoloration with acid-alcohol, which is the basis of the acid-fast stains used for pathologic identification. Acid-fast bacillus smear showing characteristic cording in Mycobacterium tuberculosis. Mycobacteria, such as M tuberculosis, are aerobic, nonspore-forming, nonmotile, facultative, curved intracellular rods measuring 0.2-0.5 m by 2-4 m. Their cell walls contain mycolic, acid-rich, long-chain glycolipids and phospholipoglycans (mycocides) that protect mycobacteria from cell lysosomal attack and also retain red basic fuchsin dye after acid rinsing (acid-fast stain). Transmission Humans are the only known reservoir for M tuberculosis. The organism is spread primarily as an airborne aerosol from an individual who is in the infectious stage of TB (although transdermal and GI transmission have been reported). In immunocompetent individuals, exposure to M tuberculosis usually results in a latent/dormant infection. Only about 5% of these individuals later show evidence of clinical disease. Alterations in the host immune system that lead to decreased immune effectiveness can allow M tuberculosis organisms to reactivate, with tubercular disease resulting from a combination of direct effects from the replicating infectious organism and from subsequent inappropriate host immune responses to tubercular antigens. Molecular typing of M tuberculosis isolates in the United States by restriction fragment-length polymorphism analysis suggests more than one third

of new patient occurrences of TB result from person-to-person transmission. The remainder results from reactivation of latent infection. Verhagen et al demonstrated that large clusters of TB are associated with an increased number of tuberculin skin testpositive contacts, even after adjusting for other risk factors for transmission.[23] The number of positive contacts was significantly lower for index cases with isoniazid-resistant TB compared with index cases with fully-susceptible TB. This suggests that some TB strains may be more transmissible than other strains and that isoniazid resistance is associated with lower transmissibility. Extrapulmonary spread Because of the ability of M tuberculosis to survive and proliferate within mononuclear phagocytes, which ingest the bacterium, M tuberculosis is able to invade local lymph nodes and spread to extrapulmonary sites, such as the bone marrow, liver, spleen, kidneys, bones, and brain, usually via hematogenous routes. Although mycobacteria are spread by blood throughout the body during initial infection, primary extrapulmonary disease is rare except in immunocompromised hosts. Infants, older persons, or otherwise immunosuppressed hosts are unable to control mycobacterial growth and develop disseminated (primary miliary) TB. Patients who become immunocompromised months to years after primary infection also can develop late, generalized disease. 2.1.3. Risk Factor Some people develop TB disease soon after becoming infected (within weeks) before their immune system can fight the TB bacteria. Other people may get sick years later, when their immune system becomes weak for another reason. Overall, about 5 to 10% of infected persons who do not receive treatment for latent TB infection will develop TB disease at some time in their lives. For persons whose immune systems are weak, especially those with HIV infection, the risk of developing TB disease is much higher than for persons with normal immune systems. Generally, persons at high risk for developing TB disease fall into two categories: Persons who have been recently infected with TB bacteria Persons with medical conditions that weaken the immune system

Persons who have been Recently Infected with TB Bacteria This includes: Close contacts of a person with infectious TB disease

Persons who have immigrated from areas of the world with high rates of TB Children less than 5 years of age who have a positive TB test Groups with high rates of TB transmission, such as homeless persons, injection drug users, and persons with HIV infection Persons who work or reside with people who are at high risk for TB in facilities or institutions such as hospitals, homeless shelters, correctional facilities, nursing homes, and residential homes for those with HIV

Persons with Medical Conditions that Weaken the Immune System Babies and young children often have weak immune systems. Other people can have weak immune systems, too, especially people with any of these conditions: HIV infection (the virus that causes AIDS) Substance abuse Silicosis Diabetes mellitus Severe kidney disease Low body weight Organ transplants Head and neck cancer Medical treatments such as corticosteroids or organ transplant Specialized treatment for rheumatoid arthritis or Crohns disease

2.1.4. Pathophysiology Once inhaled, the infectious droplets settle throughout the airways. The majority of the bacilli are trapped in the upper parts of the air ways where the mucus-secreting goblet cells exist. The mucus produced catches foreign substances,and the cilia on the surface of thecells constantly beat the mucus and its entrapped particles upward for removal. This system provides the body with an initial physical defense that prevents infection in most persons exposed to tuberculosis. Bacteria in droplets that bypass the mucociliary system and reach the alveoli are quickly surrounded and engulfed by alveolar macrophages,the most abundant immune effector cells present in alveolar spaces. These macrophages, the next line of host defense, are part of the innate immune system and provide an

opportunity for the body to destroy the invading mycobacteria and prevent infection.11Macrophages are readily available phagocytic cells that combat many pathogens without requiring previous exposure to the pathogens. Several mechanisms and macrophage receptors are involved in uptake of the mycobacteria.11 The mycobacterial lipoarabinomannan is a key ligand for a macrophage receptor. The complement system also plays a role in the phagocytosis of the bacteria. The complement protein C3 binds to the cell wall and enhances recognition of the mycobacteria by macrophages. Opsonization by C3 is rapid, even in the air spaces of a host with no previous exposure to M tuberculosis.The subsequent phagocytosis by macrophages initiates a cascade of events that results in either successful control of theinfection, followed by latent tuberculosis, or progression to active disease, called primary progressive tuberculosis.The outcome is essentially determined by the quality ofthe host defenses and the balancethat occurs between host defenses and the invading mycobacteria. After being ingested by macrophages, the mycobacteria continueto multiply slowly,with bacterialcell division occurring every 25 to 32 hours. Regardless of whether the infection becomes controlled or progresses, initial development involves production of proteolytic enzymes and cytokines by macrophages in an attempt to degrade the bacteria. Released cytokines attract T lymphocytes to the site, the cells that constitute cell-mediated immunity.Macrophages then present myco -bacterial antigens on their surface to the T cells.This initial immune process continues for 2 to 12 weeks;the microorganisms continue to grow until they reach sufficient numbers to fully elicit the cell-mediated immune response, which can be detected by a skin test. For persons with intact cellmediated immunity, the next defensive step is formation of granulomas around the M tuberculosis organisms. These nodulartype lesions form from an accumulation of activated T lymphocytes and macrophages, which creates a microenvironment that limits replication and the spread of the mycobacteria. This environment destroys macro phages and produces early solid necrosis at the center of the lesion; however, the bacilli are able to adapt to survive. In fact, M tuberculosis organisms can change their phenotypic expression, such as protein regulation, to enhance survival. By 2 or 3 weeks, the necrotic environment resembles soft cheese,often referred to caseous necrosis, and is characterized by low oxygen levels, low pH, and limited nutrients. This condition restricts further growth and establishes latency. Lesions in persons with an adequate immune system generally undergo fibrosis and calcification, successfully controlling the infection sothat the bacilli are contained in the dormant, healed lesions. Lesions in persons with less effective immunesystems

progress to primary progressive tuberculosis. For less immunocompetent persons, granuloma formation is initiated yet ultimately is unsuccessful in containing the bacilli. The necrotic tissue undergoes liquefaction, and the fibrous wall loses structural integrity. The semiliquid necrotic material can then drain into a bronchus or nearby blood vessel,leaving an air-filled cavity at theoriginal site. In patients infected with M tuberculosis, droplets can be coughed up from the bronchus andinfect other persons. If discharge into a vessel occurs, occurrence of extrapulmonary tuberculosis is likely. Bacilli can also drain into the lymphatic system and collect in the tracheobronchial lymph nodes of theaffected lung, where the organisms can form new caseous granuloma 2.1.5. Diagnostic Tests For Detecting Active Tuberculosis Consideration of tuberculosis (TB) disease as a possible diagnosis is the first step that must be taken before further evaluation, diagnosis, and management can occur. The diagnosis of TB disease is often overlooked because of the failure to consider it among possible diagnoses. While a definitive diagnosis may involve the addition of laboratory and radiographic findings, a high degree of suspicion can be based on epidemiology, medical history, and physical examination. In considering TB disease, it is also important to consider factors that may affect the typical presentation of TB, such as the patients age, nutritional status, and coexisting diseases. An individual who is suspected of having TB disease requires a complete medical evaluation, including the following: Medical history, including exposure, symptoms, previous treatment for TB, and risk factors Human immunodeficiency virus (HIV) screening Physical examination Tuberculin skin test (TST) or interferon gamma release assay (IGRA) Chest radiography Bacteriologic examination Medical History The clinician should interview patients to document their medical histories. A written record of a patients medical history should include the following:

Exposure to infectious TB Symptoms of TB disease Previous TB infection or disease Risk factors Recent medical encounters (e.g., going to the emergency department for pneumonia) Previous antibiotic therapy Exposure to infectious TB: Ask patients if they have spent time with someone with infectious TB. Question patients about whether they know of any contact in the recent or distant past with persons diagnosed with pulmonary or laryngeal TB. It is important to note that patients often refer to latent TB infection (LTBI) as TB disease. Be aware that most persons become infected with Mycobacterium tuberculosis without knowing they were exposed. Clinicians should also consider demographic factors that may increase a patients risk for exposure to TB disease and drug-resistant TB, such as country of origin, age, ethnic or racial group, occupation, and residence in congregate settings (such as a jail, homeless shelter, or refugee camp). Symptoms of TB Disease: Ask patients about their symptoms.Although TB disease does not always produce symptoms, most patients with TB disease have one or more symptoms that led them to seek medical care. When symptoms are present, they usually have developed gradually and been present for weeks or even months. Occasionally, however, TB is discovered during a medical examination for an unrelated condition, such as ruling out a cancer diagnosis (e.g., through a chest radiograph given to patients before surgery). Pulmonary General: Pulmonary and Extrapulmonary Coughing Chills Coughing up sputum Fever or blood Night sweats Pain in the chest when Loss of appetite Weight loss Weakness or easy fatigability Malaise (a feeling of Extrapulmonary The symptoms depend on part of body affected by tuberculosis (TB) disease TB of the spine may cause pain in the back.

general

TB of the kidney may cause blood in the urine. Meningeal TB may cause headaches or psychiatric symptoms. Lymphatic TB may cause swollen and tender lymph nodes, often at the base of the neck. Pleural Laryngea

Previous Latent TB Infection or TB Disease: Ask patients whether they have ever been diagnosed with or treated for TB infection or disease. Patients who have had TB disease before should be asked when they had the disease and how the disease was treated. Ask how many pills were taken per day (to determine what treatment regimen was used and whether they received injections). If the regimen prescribed was inadequate or if the patient did not follow the recommended treatment, TB may recur, and it may be resistant to one or more of the drugs used. Patients known to have a positive skin test reaction or positive Interferon Gamma Release Assay (IGRA) probably have TB infection. If they were infected within the past two years, they are at high risk for TB disease if certain immunosuppressive conditions exist or if immunosuppressive therapies are being taken.For persons previously skin tested, an increase in induration of 10 mm within a two-year period is classified as a conversion to positive or positive Interferon Gamma Release Assay (IGRA). Risk Factors for Developing TB Disease: Determine whether patients have any conditions or behaviors that are risk factors for developing TB disease Human Immunodeficiency Virus Screening

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Voluntary counseling and testing for human immunodeficiency virus (HIV) is recommended for all patients with TB. HIV counseling and testing has also been recommended for contacts of persons with TB. The Centers for Disease Control and Prevention (CDC) recommends the following: HIV screening for patients in all health-care settings after the patient is notified that testing will be performed unless the patient declines (opt-out screening). Routine HIV testing for persons suspected of having TB disease and contacts to TB patients. Persons at high risk for HIV infection should be screened for HIV at least annually Physical Examination A physical examination is an essential part of the evaluation of any patient. It cannot be used to confirm or rule out TB, but it can provide valuable information about the patients overall condition; other factors, such as human immunodeficiency virus (HIV) infection, which may affect how TB is manifested; and the presence of extrapulmonary TB. Tuberculin Skin Test and Interferon Gamma Release Assays (IGRA) Use the Mantoux tuberculin skin test (TST) or an interferon gamma release assay (IGRA) to test for M. tuberculosis infection. Note that for patients with a previous documented positive TST reaction, a TST is not necessary. However, an IGRA can be done if there is suspicion that the TST result was a false positive. Additional tests, such as chest radiography and bacteriologic examination, are required to confirm TB disease. Blood assay for Mycobacterium tuberculosis (BAMT) is a general term referring to recently developed in vitro diagnostic tests that assess for the presence of infection with M. tuberculosis. This term includes, but is not limited to IGRAs. The IGRAs currently approved by the Food and Drug Administration (FDA) and available on the market are QuantiFERON-TB Gold in tube(QFT), QuantiFERON-TB test (QFT), QuantiFERON-TB Gold test (QFT-G) and the TSPOT.TB test, which can be used in all circumstances in which the TST is used. IGRA usually can be used in place of the TST.34 Other cytokine-based immunoassays are under development and may also become useful in the diagnosis of M. tuberculosis infection. Future FDA-licensed products, in

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combination with Centers for Disease Control and Prevention (CDC)-issued recommendations, may provide additional diagnostic alternatives. The advantages of IGRA, compared with the TST, are that results can be obtained after a single patient visit, and that, because it is a blood test performed in a qualified laboratory, the variability associated with skin test reading can be eliminated. In addition, the IGRA test appears to be less affected by past bacille of Calmette-Gurin (BCG) vaccination than the TST and may eliminate the unnecessary treatment of patients with BCG-related false-positive results. However, the IGRA test has practical limitations that include the need to draw blood and to ensure its receipt in a qualified laboratory in time for testing. For IGRA tests, the blood must be incubated with the test antigens less than 12 hours after collection, while the lymphocytes are viable. (Note: When newer IGRA tests are available, this time frame may differ.) For both the TST and IGRA, additional tests, such as chest radiography and bacteriologic examination, are required to confirm TB disease. Persons with a positive TST result, regardless of signs and symptoms, should be evaluated for TB disease before LTBI is diagnosed. At a minimum, a chest radiograph should be examined for abnormalities consistent with TB disease. A negative TST does not rule out TB diseaseas many as 20% of patients with TB disease have a negative TST reaction. A negative TST result should not be used alone to exclude M. tuberculosis infection in persons with symptoms or signs suggestive of TB disease. Medical evaluation of such persons should include a history and physical examination, chest radiograph, bacteriologic studies, serology for human immunodeficiency virus (HIV), and, when indicated, other tests or studies Chest Radiography A posterior-anterior radiograph of the chest is the standard view used for the detection and description of chest abnormalities in adults. In some instances, other views (e.g., lateral, lordotic) or additional studies (e.g., computed tomography [CT] scans) may be necessary. Children younger than 5 years of age should receive posterior-anterior and lateral radiographs. Certain abnormalities on chest radiographs are suggestive, but are not diagnostic, of TB. In pulmonary TB, radiographic abnormalities are often seen in the apical and posterior segments of the upper lobe or in the superior segments of the lower lobe. However, lesions may appear anywhere in the lungs and may differ in size,

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shape, density, and presence or absence of cavitation, especially in HIV-infected and other immunosuppressed persons. In HIV-infected persons, pulmonary TB may present atypically on the chest radiograph. For example, TB may cause opacities without cavities in any lung zone, or it may cause mediastinal or hilar lymphadenopathy with or without accompanying opacities and/or cavities. In HIVinfected persons, almost any abnormality on a chest radiograph may indicate TB. In fact, the radiograph of an HIV-infected person with TB disease may even appear entirely normal. Bacteriologic Examination Specimens For Diagnosing Tuberculosis Disease Suspected Diagnosis Pulmonary or laryngeal tuberculosis (TB) Specimen Needed Sputum (phlegm from deep in the lungs) samples for smear and culture examination. If a diagnosis of pulmonary TB cannot be established from sputum smear, other procedures may be necessary, including nucleic acid amplification (NAA), bronchoscopy, and gastric aspiration in children. Depending on the anatomical site, other clinical specimens are necessary, such as: Urine Cerebrospinal fluid Pleural fluid Pus or other aspirated fluid Biopsy specimens Blood

Extrapulmonary TB

Bacteriologic Tests Used In Diagnosing Tuberculosis Disease Test Acid-Fast Bacilli (AFB) Smear Description Provides the physician with a preliminary confirmation of the diagnosis. It usually is the first bacteriologic evidence of the presence of mycobacteria in a clinical specimen. If positive, gives a semiquantitative

Laboratory Turnaround Times Within 24 hours from receipt of specimen in the laboratory

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Nucleic Acid Amplification (NAA) Assay

Culture

estimate of the number of bacilli being excreted (which is of vital clinical and epidemiologic importance in assessing the patients infectiousness). A test done on sputum specimens for the direct and rapid identification of the Mycobacterium tuberculosis complex. Allows for the amplification of specific target sequences of nucleic acids that will be detected by a nucleic acid probe. Does not replace the need for routine AFB smear and culture Usually necessary for species identification of all clinical specimens suspected of containing mycobacteria. Is required for drug susceptibility testing and genotyping For first-line drugs: Is performed on initial isolates of all patients to identify an effective antituberculosis regimen. For both first-line and second-line drugs: Is repeated on interim isolates when a patient remains culture-positive after 3 months of treatment Allows rapid confirmation of MDR TB through the identification of genetic mutations associated with RIF and INH resistance MDR case. Also the DRSS examines the genetic loci that are associated with resistance to the most effective second-line drugs, fluroquinolones (FQ) and the injectables amakacin (AMK), kanamycin (KAN) and capreomycin (CAP) will be examined.

Within 2-3 working days from receipt of specimen in the laboratory

Drug Susceptibility Testing

Mycobacterial growth detection: within 14 days from specimen collection Identification of mycobacteria: within 21 days from specimen Collection First-line drugs: within 30 daysfrom specimen collection. Second-line drugs: within 4 weeks from date of request.

Drug Resistance Screening by Sequencing (DRSS)

DRSS results are available within 3-4 business days from the receipt of specimen at the WA PHL laboratory. DRSS is a presumptive test and needs to be confirmed by traditional susceptibility testing. WAPHL performs confirmation for the First line drugs (up to 14 days MTBC identification) and Second line drug (28 days from the receipt of the specimen [reference cultures] or MTBC identification).

2.1.6. TB Disease Treatment Regimens Anti-tuberculosis drugs

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Anti-tuberculosis treatment is divided into two phases: an intensive (initial) phase and a continuation phase. The purpose of the intensive phase is to rapidly eliminate the majority of organisms and to prevent the emergence of drug resistance. The intensive phase uses more drugs. The purpose of the continuation phase is to eradicate the dormant organisms. Fewer drugs are generally used in the continuation phase because the risk of acquiring drug resistance is low, as most of the organisms have already been eliminated. Either phase can be give daily or three times weekly. Table 1 shows the essential anti-tuberculosis drugs and their recommended doses. The need for better data on anti-tuberculosis drug pharmacokinetics in children is highlighted by the variations in national recommendations for drug doses in children, particularly for isoniazid (INH) (some guidelines, such as those of the American Thoracic Society, recommend a dose of INH of 1015 mg/kg). Thiacetazone is no longer recommended as part of a rstline regimen to treat TB, as it has been associated with severe reactions (Stevens-Johnson Syndrome) in adults and children with TB who are coinfected with the human immunodeciency virus (HIV).

Table 1 Doses of rst-line anti-tuberculosis drugs in adults and children Recommended dose in mg/kg body weight (range) Essential drug Daily Isoniazid (H) Rifampicin (R) Pyrazinamide (Z) Ethambutol (E) Streptomycin (S) Treatment regimens 5 (46) max. 300 mg daily 10 (812) max. 600 mg daily 25 (2030) 20 (1525)* 15 (1218)

Three times weekly 10 (812) 10 (812) max. 600 mg daily 35 (3040) 30 (2535) 15 (1218)

The recommended treatment regimens for each TB diagnostic category are generally the same for childrenas for adults. New cases fall under Category I (newsmear-positive pulmonary TB; new smear-negative pulmonary TB with extensive parenchymal involvement; severe forms of EPTB; severe concomitant

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HIV disease) or Category III (new smear-negative pulmonary TBother than in Category I; less severe forms of EPTB). Most children with TB have uncomplicated(smear-negative) pulmonary/intrathoracic TB or nonsevere forms of EPTB, and therefore fall under diagnostic Category III. Those children with smear-positivepulmonary TB, extensive pulmonary involvement, orsevere forms of EPTB (e.g., abdominal or bone/jointTB) fall under diagnostic Category I. Children with TBmeningitis and miliary TB deserve special consideration(see below). Previously treated cases fall under diagnostic Category II (previously treated smear-positive pulmonary TB) or IV (chronic and multidrug resistant [MDR] TB). Table 2 shows the recommended treatment regimens for each treatment category, based on the best available evidence. There is a standard code for TB treatment regimens,which uses an abbreviation for each anti-tuberculosis drug. A regimen consists of two phases. The number in front of each phase represents the duration of that phase in months. A subscript number (e.g., 3) following a letter (drug abbreviation) is the number of doses per week of that drug. If there is no subscript number following a letter, treatment with that drug is daily. An alternative drug (or drugs) appears as a letter (or letters) in parentheses. Example: 2HRZ/4H3R3 The initial phase is 2HRZ. The duration of the initial phase is 2 months. Drug treatment is daily (no subT script numbers after the letters) with INH (H), rifampicin (R, RMP) and pyrazinamide (Z, PZA). The continuation phase is 4H3R3. The duration of the continuation phase is 4 months, with H and R given three times weekly (number in subscript after the letters). Table 2 Recommended treatment regimens for each diagnostic category TB diagnostic category TB cases Regimen (daily or 3 times weekly)* Intensive phase Continuation phase smear-positive 2HRZE 4HR or 6HE

New pulmonary TB New smear-negative pulmonary TB with extensive parenchymal involvement Severe forms of EPTB (other than TB meningitissee below)

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Severe concomitant HIV disease TB meningitis Previously treated smearpositive pulmonary TB: relapse treatment after interruption treatment failure New smear-negative pulmonary TB (other than in category I) Less severe forms of EPTB Chronic and MDR-TB

2RHZS 4RH 2HRZES/1HRZE 5HRE

2HRZ

4HR or 6HE

Specially designed standardised or individualised regimens (see treatment guidelines for MDR-TB3)

Adjunctive treatment with corticosteroids Corticosteroids may be used for the management of some complicated forms of TB, e.g., tuberculous meningitis (TBM), the complications of airway obstruction by TB lymph glands, and TB pericarditis. In advanced TBM cases, corticosteroids have been shown to improve survival and reduce morbidity, and are thus recommended in all cases of TBM. The drug most frequently used is prednisone, in a dosage of 2 mg/kg/day (maximum dosage 60 mg/day) for 4 weeks. The dose should then be slowly reduced (tapered off) over 12 weeks before stopping.

TREATMENT ADMINISTRATION AND ADHERENCE Children, their parents and other family members and other care givers should be educated about TB and the importance of completing treatment. The support of the childs parents and immediate family is vital to ensure a satisfactory outcome of treatment. Preferably someone other than the childs parent or immediate family should observe or administer treatment. All children should receive treatment free of charge, whether or not the child is smear-positive at diagnosis. Fixed-dose combinations (FDCs) should be used whenever possible to improve simplicity and adherence. Patient treatment cards are recommended for documenting treatment adherence. Children with severe forms of TB should be hospitalised for intensive management where possible. Conditions that merit hospitalisation include: 1) TB meningitis and miliary TB, preferably for the rst 2 months, 2) any child with

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respiratory distress, 3) spinal TBand 4) severe adverse events, such as clinical signs of hepatotoxicity (e.g., jaundice). If it is not possible toensure good adherence and treatment outcome as an out-patient, some children may require hospitalisation for social or logistical reasons. FOLLOW-UP Ideally, each child should be assessed by the National Tuberculosis Programme (NTP) (or those designated by the NTP to provide treatment) at least at the following intervals: 2 weeks after treatment initiation, at the end of the intensive phase, and every 2 months until treatment completion. The assessment should include, at a minimum, a symptom assessment, an assessment of adherence, enquiry about any adverse events, and weight measurement. Medication dosages should be adjusted to account for any weight gain. Adherence should be assessed by reviewing the treatment card. A follow-up sputum smear for microscopy at 2 months should be obtained for any child who was smearpositive at diagnosis. Follow-up chest radiographs are not routinely required in children, particularly as many children willhave a slow radiological response to treatment. A child who is not responding to TB treatment should be referred for further assessment and management. These children may have drug-resistant TB, an unusual complication of pulmonary TB, other causes of lung disease, or problems with treatment adherence. The NTP is responsible for organising treatment in line with the Stop TB Strategy, and ensuring the recording and reporting of cases and their outcomes. Good communication is necessary between the NTP and clinicians treating children with TB. Adverse events notedby clinicians should be reported to the NTP. Immune reconstitution Sometimes referred to as a paradoxical reaction, thistemporary exacerbation of symptoms, signs or radiographic manifestations sometimes occurs after beginning anti-tuberculosis treatment. This can simulate worsening disease, with fever, and increased size of lymph nodes or tuberculomas. Immune reconstitution can be brought about by improved nutritional statusor by the antituberculosis treatment itself. Clinical deterioration due to immune reconstitution can occur after initiation of antiretroviral therapy (ART) in HIVinfected children with TB, and is known as the immune reconstitution inammatory syndrome (IRIS). Antituberculosis treatment should be continued, although in some cases the addition of corticosteroids might be useful. If in doubt, refer the child to the next level of care.

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Adverse events Adverse events caused by anti-tuberculosis drugs are much less common in children than in adults. The most important adverse event is the development of hepatotoxicity, which can be caused by INH, RMP, or PZA. Serum liver enzyme levels should not be monitored routinely, as asymptomatic mild elevation of serum liver enzymes (less than 5 times normal values) is not an indication to stop treatment. However, the occurrence of liver tenderness, hepatomegaly or jaundice should lead to investigation of serum liver enzyme levels and the immediate stopping of all potentially hepatotoxic drugs. Patients should be screened for other causes of hepatitis,and no attempt should be made to reintroduce these drugs until liver functions have normalised. An expert should be involved in the further management of such cases. If treatment for TB needs to be continued for severe forms of TB, non-hepatotoxic anti-tuberculosis drugs should be introduced (e.g., ethambutol [E, EMB], an aminoglycoside and a uoroquinolone). INH may cause symptomatic pyridoxine deciency, particularly in severely malnourished children and HIVinfected children on highly active antiretroviral ther- apy (HAART). Supplemental pyridoxine (510 mg/day) is recommended in 1) malnourished children, 2)HIV-infected children, 3) breastfeeding infants, and 4) pregnant adolescents.

2.1.7. Prevention of TB Disease The key method of preventing tuberculosis (TB) is prompt identification and treatment of patients with TB. Other strategies include patient education, treatment of latent infection, and vaccination. The World Health Organization (WHO) launched the Stop TB strategy in 2006 (modelled after the directly observed theraphy [DOT] strategy) and the core components include pursuing high-quality DOT expansion and enhancement; addressing TB and human immunodeficiency (HIV) infection, multidrug-resistant (MDR) TB, and other challenges; contributing to health system strengthening; engaging all care providers; empowering people with TB; and enabling and promoting research. Patient education Thoroughly educate patients regarding compliance to therapy, adverse effects of medications, and follow-up care. Treatment of latent TB infection

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Recommendations for preventive therapy are based on a comparative analysis of the risk of administration of isoniazid (INH) versus the risk of acquiring the disease. Adults with a positive tuberculin skin test (TST) result and no clinical or radiographic manifestations who are receiving INH therapy have been demonstrated to have 54-88% protection against the development of the disease, whereas children have been shown to have 100% protection. The risk of acquisition of TB is particularly high in very young children (< 5 y) and in the adolescent population. Thus, patients in these age groups with a positive TST result and no other manifestations should receive INH therapy. Active TB should be carefully excluded before the initiation of preventive therapy. For recent contacts of patients with contagious TB (ie, in the past 3 mo), INH therapy is indicated even if the TST result is negative. This is especially true for contacts who are infected with HIV or for household contacts younger than 5 years. Household contacts of any age should be considered for INH therapy if they are from a high-prevalence area, even if the TST result is negative. The recommendations from the American Academy of Pediatrics (AAP) are to administer 9 months of therapy. The drug of choice is INH. A treatment period of 12 months is recommended for patients with HIV infection. For the management of contacts of INH-resistant cases, rifampin is recommended for 6 months in children. In case of a high probability of infection with MDR TB, observation is recommended, because none of the other drugs have been evaluated for preventive therapy. Several drugs have been used in these circumstances, including pyrazinamide, fluoroquinolones, and ethambutol, depending on the susceptibility patterns.

Vaccination The bacille Calmette-Gurin (BCG) vaccine is available for the prevention of disseminated TB. BCG is a live vaccine prepared from attenuated strains of M bovis. The major role of BCG vaccination is the prevention of serious and lifethreatening disease such as disseminated TB and TB meningitis in children. The BCG vaccine does not prevent infection with M tuberculosis.

20

Although the BCG vaccine has been in use since 1921 and approximately 3 billion doses have been administered, its efficacy continues to be debated. Several trials have been performed to assess the efficacy of the vaccine, and results vary. However, 2 meta-analyses of the various trials concluded that the vaccine is efficacious against miliary and meningeal TB.[18] Controversy surrounds the efficacy of BCG vaccination against pulmonary TB. The WHOs Expanded Program on Immunization recommends the administration of BCG at birth. The vaccine is used in more than 100 countries. In the United States, BCG vaccination is currently recommended only in certain situations, including the following: Child has negative HIV and TST results, is exposed to persons with contagious MDR (resistant to INH and rifampin) pulmonary TB, and cannot be removed from the exposure Child has negative HIV and TST results, is exposed to persons with untreated or ineffectively treated contagious pulmonary TB, and cannot be removed from the exposure or treated with anti-TB medication From birth to age 2 months, administration of BCG does not require a previous TST. Thereafter, a TST is mandatory before vaccination. Adverse reactions due to the vaccine include subcutaneous abscess formation and the development of lymphadenopathy. Rare complications, such as osteitis of the epiphyses of the long bones and disseminated TB, may necessitate administration of anti-TB therapy, except for pyrazinamide. Contraindications to the administration of the vaccine include immunosuppressed conditions such as primary or secondary immunodeficiency, including steroid use and HIV infection. However, in areas of the world where the risk of TB is high, the WHO recommends using the BCG vaccine in children who have asymptomatic HIV infection.

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2.2. MALNUTRITION Protein-energy malnutrition (PEM) in young children is currently the most important nutritional problem in most countries in Asia, Latin America, the Near East and Africa. Energy deficiency is the major cause. No accurate figures exist on the world prevalence of PEM, but World Health Organization (WHO) estimates suggest that the prevalence of PEM in children under five years of age in developing countries has fallen progressively, from 42.6 percent in 1975 to 34.6 percent in 1995. However, in some regions this fall in percentage has not been as rapid as the rise in population; thus in some regions, such as Africa and South Asia, the number of malnourished children has in fact risen. In fact the number of underweight children worldwide has risen from 195 million in 1975 to an estimated 200 million at the end of 1994, which means that more than onethird of the world's under-five population is still malnourished. Failure to grow adequately is the first and most important manifestation of PEM. It often results from consuming too little food, especially energy, and is frequently aggravated by infections. A child who manifests growth failure may be shorter in length or height or lighter in weight than expected for a child of his or her age, or may be thinner than expected for height. The term PEM is used to describe a broad array of clinical conditions ranging from the mild to the serious. At one end of the spectrum, mild PEM manifests itself mainly as poor physical growth in children; at the other end of the spectrum, kwashiorkor (characterized by the presence of oedema) and nutritional marasmus (characterized by severe wasting) have high case fatality rates. It has been known for centuries that grossly inadequate food intake during famine and food shortages leads to weight loss and wasting and eventually to death from starvation. However, it was not until the 1930s that Cicely Williams, working in Ghana, described in detail the condition she termed "kwashiorkor" (using the local Ga word meaning "the disease of the displaced child"). In the 1950s kwashiorkor began to get a great deal of attention. It was often described as the most important form of malnutrition, and it was believed to be caused mainly by protein deficiency. The solution seemed to be to make more protein-rich foods available to children at risk. This stress on kwashiorkor and on protein led to a relative neglect of nutritional marasmus and adequate food and energy intakes for children. The current view is that most PEM is the result of inadequate intake or poor utilization of food and energy, not a deficiency of one nutrient and not usually simply a lack of dietary protein. It has also been increasingly realized that infections contribute importantly to PEM. Nutritional marasmus is now recognized to be often more prevalent than kwashiorkor. It is unknown why a given child may develop one syndrome as opposed to the other, and it is now seen that these two serious clinical forms of PEM constitute only the small tip of the

22

iceberg. In most populations studied in poor countries, the point prevalence rate for kwashiorkor and nutritional marasmus combined is 1 to 5 percent, whereas 30 to 70 percent of children up to five years of age manifest what is now termed mild or moderate PEM, diagnosed mainly on the basis of anthropometric measurements. 2.2.1. Causes and epidemiology PEM, unlike the other important nutritional deficiency diseases, is a macronutrient deficiency, not a micronutrient deficiency. Although termed PEM, it is now generally accepted to stem in most cases from energy deficiency, often caused by insufficient food intake. Energy deficiency is more important and more common than protein deficiency. It is very often associated with infections and with micronutrient deficiencies. Inadequate care, for example infrequent feeding, may play a part. The cause of PEM (and of some other deficiency diseases prevalent in developing countries) should not, however, be viewed simply in terms of inadequate intake of nutrients. For satisfactory nutrition, foods and the nutrients they contain must be available to the family in adequate quantity; the correct balance of foods and nutrients must be fed at the right intervals; the individual must have an appetite to consume the food; there must be proper digestion and absorption of the nutrients in the food; the metabolism of the person must be reasonably normal; and there should be no conditions that prevent body cells from utilizing the nutrients or that result in abnormal losses of nutrients. Factors that adversely influence any of these requisites can be causes of malnutrition, particularly PEM. The aetiology, therefore, can be complex. Certain factors that contribute to PEM, particularly in the young child, are related to the host, the agent (the diet) and the environment. The underlying causes could also be categorized as those related to the child's food security, health (including protection from infections and appropriate treatment of illness) and care, including maternal and family practices such as those related to frequency of feeding, breastfeeding and weaning. Some examples of factors involved in the aetiology of PEM are: the young child's high needs for both energy and protein per kilogram relative to those of older family members; inappropriate weaning practices; inappropriate use of infant formula in place of breastfeeding for very young infants in poor families;

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staple diets that are often of low energy density (not infrequently bulky and unappetizing), low in protein and fat content and not fed frequently enough to children; inadequate or inappropriate child care because of, for example, time constraints for the mother or lack of knowledge regarding the importance of exclusive breastfeeding; inadequate availability of food for the family because of poverty, inequity or lack of sufficient arable land, and problems related to intrafamily food distribution; infections (viral, bacterial and parasitic) which may cause anorexia, reduce food intake, hinder nutrient absorption and utilization or result in nutrient losses; famine resulting from droughts, natural disasters, wars, civil disturbances, etc. Prematurity or low birth weight may predispose the child to the development of nutritional marasmus. Failure of breastfeeding because of death of the mother, separation from the mother or lack of or insufficient breastmilk may be causes in poor societies where breastfeeding is often the only feasible way for mothers to feed their babies adequately. An underlying cause of PEM is any influence that prevents mothers from breastfeeding their newborn infants when they live in households where proper bottle-feeding may be difficult or hazardous. Therefore promotion of infant formula and insufficient support of breastfeeding by the medical profession and health services may be factors in the aetiology of marasmus. Prolonged exclusive breastfeeding without the introduction of other foods after six months of age may also contribute to growth faltering, PEM and eventually nutritional marasmus. The view that kwashiorkor is the result of protein deficiency and nutritional marasmus the result of energy deficiency is an oversimplification, as the causes of both conditions are complex. Both endogenous and exogenous causes are likely to influence whether a child develops nutritional marasmus, kwashiorkor or the intermediate form known as marasmic kwashiorkor. In a child who consumes much less food than required for his or her energy needs, energy is mobilized from both body fat and muscle. Gluconeogenesis in the liver is enhanced, and there is loss of subcutaneous fat and wasting of muscles. It has been suggested that under these circumstances, especially when protein intake is very low relative to carbohydrate intake (with the situation perhaps aggravated by nitrogen losses from infections), various metabolic changes take place which contribute to the development of oedema. More sodium and more water are retained, and much of the water collects outside the cardiovascular system in the tissues, which results in pitting oedema. The actual role of infection has not been

24

adequately explained, but certain infections cause major increases in urinary nitrogen, which derives from amino acids in muscle tissue. There is not yet broad agreement on the actual cause of the oedema that is the hallmark of kwashiorkor. Most researchers agree that potassium deficiency and sodium retention are important in the pathogenesis of oedema. Some evidence supports the classical argument that oedematous malnutrition is a sign of inadequate protein intake. For example, oedema, fatty liver and a kwashiorkorlike condition can be induced in pigs and baboons on a protein-deficient diet. Epidemiological evidence also shows higher rates of kwashiorkor in Uganda, where the staple diet is plantain, which is very low in protein, than in neighbouring areas where the staple food is a cereal. Recently two new theories have been advanced to explain the cause of kwashiorkor. The first is that kwashiorkor is due to aflatoxin poisoning. The second is that free radicals are important in the pathogenesis of kwashiorkor; it has been hypothesized that most of the clinical features of kwashiorkor could be caused by an excess free radical stress. This new, relatively untested theory also suggests, however, that kwashiorkor, even if produced by free radicals, is likely to occur only in children who have inadequate food intake and are subjected to infection. Thus even if this theory were to be proved correct, it would merely explain a mechanism for the pathogenesis of kwashiorkor. It would not change the fact that improving diet and reducing infection lead to significant reduction in both kwashiorkor and nutritional marasmus. Neither the aflatoxin nor the free radical theory has been proved experimentally, nor is there adequate convincing research to uphold the view of individual dysadaptation as the cause of severe PEM. Surprisingly, no studies have been able to give conclusive proof of either similarities or differences in dietary consumption between children who develop kwashiorkor with oedema and those who show clinical signs of nutritional marasmus without any oedema. In severe PEM there is usually biochemical evidence, and often clinical evidence, of micronutrient deficiencies, which is not surprising in a child or adult who consumes a grossly inadequate diet. In both nutritional marasmus and kwashiorkor (and also in moderate PEM), clinical examinations or biochemical tests often give clear evidence of, for example, vitamin A deficiency, nutritional anaemia and/or zinc deficiency. However, there is little indication that any one micronutrient deficiency is the main cause of PEM or is by itself responsible for the oedema of kwashiorkor. Irrespective of which theory of aetiology may be proved correct, improving the quantity of food consumed, taking steps to ensure that diets are nutritionally well balanced and controlling infection all help to prevent PEM.

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2.2.2. Manifestations and clinical picture Mild and moderate PEM The condition of PEM is often likened to an iceberg, of which 20 percent is visible above the water and about 80 percent submerged. The severe forms of PEM - kwashiorkor, nutritional marasmus and marasmic kwashiorkor - constitute the top, exposed part of the iceberg: they are relatively easy for a doctor or health worker to diagnose simply from their clinical manifestations, described below. On the other hand, children with moderate or mild malnutrition often do not have clear clinical manifestations of malnutrition; rather, they are shorter and/or thinner than would be expected for their age, and they may have deficits in psychological development and perhaps other signs not easy to detect. Mild and moderate PEM are diagnosed mainly on the basis of anthropometry, especially using measurements of weight and height and sometimes other measurements such as arm circumference or skinfold thickness. As shown by the iceberg diagram (Figure 5), the prevalence of highly visible, serious PEM (kwashiorkor, marasmic kwashiorkor and nutritional marasmus) is usually between about 1 and 5 percent, except in famine areas. In contrast, moderate and mild malnutrition in many countries of sub-Saharan Africa and South Asia add up to 30 to 70 percent. In these areas often only 15 to 50 percent of young children between six months and 60 months of age do not have evidence of PEM. The diagram illustrates that both energy deficiency and protein deficiency play a part, but that energy deficiency is more important. It suggests that protein deficiency plays a greater part in kwashiorkor and energy deficiency in nutritional marasmus. The percentage of children classified as having severe, moderate and mild PEM depends on how these terms are defined. The two severe forms of malnutrition, kwashiorkor and nutritional marasmus, have very different appearances and clinical features as described below. It is generally agreed that the hallmark of kwashiorkor is pitting oedema, and the overriding feature of nutritional marasmus is severe underweight. Children who have both oedema and severe underweight are diagnosed as having marasmic kwashiorkor.

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FIGURE 5. PEM iceberg

The so-called Wellcome classification of severe forms of PEM has been widely used for over 20 years (see Table 19). It has the advantage of simplicity because it is based on only two measures, namely the percentage of standard weight for age and the presence or absence of oedema. The category "undernourished" includes children who have moderate or moderately severe PEM but no oedema and whose weight is above 60 percent of the standard. Today a cut-off point using standard deviations (SD) is considered more appropriate than percentage of standard, but not many children would be reclassified. In the 1950s and 1960s the degree of malnutrition was almost always based on the child's percentage of standard weight for age. In Latin America and elsewhere the Gomez classification was very widely used (Table 20). In the early 1970s a number of nutrition workers began to suggest that judging the degree of malnutrition only on the basis of weight for age had many disadvantages. A method was suggested that distinguished three categories of mild to moderate PEM based on weight and height measurements of children. Subsequently these categories came to be known as follows: wasting: acute current, short-duration malnutrition, where weight for age and weight for height are low but height for age is normal;

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stunting: past chronic malnutrition, where weight for age and height for age are low but weight for height is normal; wasting and stunting: acute and chronic or current long-duration malnutrition, where weight for age, height for age and weight for height are all low. TABLE 19 Wellcome classification of severe forms of protein-energy malnutrition Percentage of standard weight for Oedema present age 60-80 Kwashiorkor <60 Marasmic kwashiorkor Oedema absent Undernourishment Nutritional marasmus

TABLE 20 The Gomez classification of malnutrition based on weight-for-age standards Classification Normal Grade I (mild malnutrition) Grade IIIa (severe malnutrition)
a

Percentage of standard weight for age >90 75-89.9 <<60

Grade II (moderate malnutrition) 60-74.9

J. Bengoa of WHO suggested that all children with oedema be placed in Grade 111. This became known as the Bengoa modification. This classification makes a distinction between current and past influences on nutritional status. It helps the examiner assess the likelihood that supplementary feeding will markedly improve the nutritional status of the child, and it gives the clinician some clue as to the history of the malnutrition in the patient. It also has advantages for nutritional surveys and surveillance. In general, stunting is more prevalent than wasting worldwide. The assessment of nutritional status, it is now generally recommended that malnutrition be judged on the basis of SD below the growth standards of the United States National Center for Health Statistics (NCHS) as published by WHO. In country reports published based on weight for age alone, "underweight" is commonly used to denote weight below 2 SD of the NCHS standards in children up to five years of age. In a normal distribution it is expected that 2 to 3 percent of children will fall below the -2 SD cut-off point. Prevalence above that

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level suggests that there is a nutritional problem in the population assessed. If measurements are also taken of length or height, then the children can be further divided into those who are wasted, stunted, or wasted and stunted. Policy-makers and health workers need to decide which growth standards to use as a yardstick for judging malnutrition and for surveys, monitoring and surveillance. In recent years the WHO/NCHS growth standards (which do not differ very much from previously used standards, such as the Harvard and Denver growth standards) have gained increasing acceptance. The international growth standards have been found to be applicable for developing countries, as evidence shows that the growth of privileged children in developing countries does not differ importantly from these standards, and that the poorer growth seen among the underprivileged results from social factors, including the malnutritioninfection complex, rather than from ethnic or geographic differences. The functional significance of mild or moderate PEM is still not fully known. Studies from several countries show that the risk of mortality increases rather steadily with worsening nutritional status as indicated by anthropometric measures. Recent investigations in Guatemala indicated that teenagers who had manifested poor growth when examined in early childhood were smaller in stature, did less well at school, had poorer physical fitness and had lower scores on psychological development tests than children from the same villages who grew better as young children. These results suggest long-term consequences of PEM in early childhood. The attempt to control the extent and severity of PEM using many different strategies and actions is at the heart of nutritional programmes and policies in most developing countries. The reduction and eventual prevention of mild or moderate malnutrition will automatically reduce severe malnutrition. Thus, although it may be tempting (particularly for doctors and other health workers) to put major emphasis on the control of nutritional marasmus and kwashiorkor, resources are often better spent on controlling mild and moderate PEM, which will in turn reduce severe PEM. 2.2.3. Kwashiorkor Kwashiorkor is one of the serious forms of PEM. It is seen most frequently in children one to three years of age, but it may occur at any age. It is found in children who have a diet that is usually insufficient in energy and protein and often in other nutrients. Often the food provided to the child is mainly carbohydrate; it may be very bulky, and it may not be provided very frequently. Kwashiorkor is often associated with, or even precipitated by, infectious diseases. Diarrhoea, respiratory infections, measles, whooping cough, intestinal parasites and other infections are common underlying causes of PEM and may precipitate children into either kwashiorkor or nutritional marasmus. These

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infections often result in loss of appetite, which is important as a cause of serious PEM. Infections, especially those resulting in fever, lead to an increased loss of nitrogen from the body which can only be replaced by protein in the diet. Clinical signs of kwashiorkor Kwashiorkor is relatively easy to diagnose based on the child's history, the symptoms reported and the clinical signs observed (Figure 6). Laboratory tests are not essential but do throw more light on each case. All cases of kwashiorkor have oedema to some degree, poor growth, wasting of muscles and fatty infiltration of the liver. Other signs include mental changes, abnormal hair, a typical dermatosis, anaemia, diarrhoea and often evidence of other micronutrient deficiencies. Oedema. The accumulation of fluid in the tissues causes swelling; in kwashiorkor this condition is always present to some degree. It usually starts with a slight swelling of the feet and often spreads up the legs. Later, the hands and face may also swell. To diagnose the presence of oedema the medical attendant presses with a finger or thumb above the ankle. If oedema is present the pit formed takes a few seconds to return to the level of the surrounding skin.

Poor growth. Growth failure always occurs. If the child's precise age is known, the child will be found to be shorter than normal and, except in cases of gross oedema, lighter in weight than normal (usually 60 to 80 percent of standard or below 2 SD). These signs may be obscured by oedema or ignorance of the child's age.

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FIGURE 6. Characteristics of kwashiorkor

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Wasting. Wasting of muscles is also typical but may not be evident because of oedema. The child's arms and legs are thin because of muscle wasting.

Fatty infiltration of the liver. This condition is always found in post-mortem examination of kwashiorkor cases. It may cause palpable enlargement of the liver (hepatomegaly).

Mental changes. Mental changes are common but not invariably noticed. The child is usually apathetic about his or her surroundings and irritable when moved or disturbed. The child prefers to remain in one position and is nearly always miserable and unsmiling. Appetite is nearly always poor.

Hair changes. The hair of a normal Asian, African or Latin American child is usually dark black and coarse in texture and has a healthy sheen that reflects light. In kwashiorkor, the hair becomes silkier and thinner. African hair loses its tight curl. At the same time it lacks lustre, is dull and lifeless and may change in colour to brown or reddish brown. Sometimes small tufts can be easily and almost painlessly plucked out. On examination under a microscope, plucked hair exhibits root changes and a narrower diameter than normal hair. The tensile strength of the hair is also reduced. In Latin America bands of discoloured hair are reported as a sign of kwashiorkor. These reddish-brown stripes have been termed the "flag sign" or "signa bandera".

Skin changes. Dermatosis develops in some but not all cases of kwashiorkor. It tends to occur first in areas of friction or of pressure such as the groin, behind the knees and at the elbow. Darkly pigmented patches appear, which may peel off or desquamate. The similarity of these patches to old sun-baked, blistered paint has given rise to the term "flaky-paint dermatosis". Underneath the flaking skin are atrophic depigmented areas which may resemble a healing burn.

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Anaemia. Most cases have some degree of anaemia because of lack of the protein required to synthesize blood cells. Anaemia may be complicated by iron deficiency, malaria, hookworm, etc.

Diarrhoea. Stools are frequently loose and contain undigested particles of food. ometimes they have an offensive smell or are watery or tinged with blood.

Moonface. The cheeks may appear to be swollen with either fatty tissue or fluid, giving the characteristic appearance known as "moonface".

Signs of other deficiencies. In kwashiorkor some subcutaneous fat is usually palpable, and the amount gives an indication of the degree of energy deficiency. Mouth and lip changes characteristic of vitamin B deficiency are common. Xerosis or xerophthalmia resulting from vitamin A deficiency may be seen. Deficiencies of zinc and other micronutrients may occur.

2.2.4. Nutritional marasmus In most countries marasmus, the other severe form of PEM, is now much more prevalent than kwashiorkor. In marasmus the main deficiency is one of food in general, and therefore also of energy. It may occur at any age, most commonly up to about three and a half years, but in contrast to kwashiorkor it is more common during the first year of life. Nutritional marasmus is in fact a form of starvation, and the possible underlying causes are numerous. For whatever reason, the child does not get adequate supplies of breastmilk or of any alternative food. Perhaps the most important precipitating causes of marasmus are infectious and parasitic diseases of childhood. These include measles, whooping cough, diarrhoea, malaria and other parasitic diseases. Chronic infections such as tuberculosis may also lead to marasmus. Other common causes of marasmus are premature birth, mental deficiency and digestive upsets such as malabsorption or vomiting. A very common cause is early cessation of breastfeeding.

Clinical features of nutritional marasmus

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The important features of kwashiorkor and nutritional marasmus are compared in Table 21. The following are the main signs of marasmus. Poor growth In all cases the child fails to grow properly. If the age is known, the weight will be found to be extremely low by normal standards (below 60 percent or -3 SD of the standard). In severe cases the loss of flesh is obvious: the ribs are prominent; the belly, in contrast to the rest of the body, may be protuberant; the face has a characteristic simian (monkeylike) appearance; and the limbs are very emaciated. The child appears to be skin and bones. An advanced case of the disease is unmistakable, and once seen is never forgotten.

Wasting. The muscles are always extremely wasted. There is little if any subcutaneous fat left. The skin hangs in wrinkles, especially around the buttocks and thighs. When the skin is taken between forefinger and thumb, the usual layer of adipose tissue is found to be absent.

Alertness. Children with marasmus are quite often not disinterested like those with kwashiorkor. Instead the deep sunken eyes have a rather wide-awake appearance. Similarly, the child may be less miserable and less irritable.

Appetite. The child often has a good appetite. In fact, like any starving being, the child may be ravenous. Children with marasmus often violently suck their hands or clothing or anything else available. Sometimes they make sucking noises.

Anorexia. Some children are anorexic.

Diarrhoea. Stools may be loose, but this is not a constant feature of the disease. Diarrhoea of an infective nature, as mentioned above, may commonly have been a precipitating factor.

Anaemia.

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Anaemia is usually present.

Skin sores. There may be pressure sores, but these are usually over bony prominences, not in areas of friction. In contrast to kwashiorkor, there is no oedema and no flaky-paint dermatosis in marasmus.

Hair changes. similar to those in kwashiorkor can occur. There is more frequently a change of texture than of colour.

Dehydration. Although not a feature of the disease itself, dehydration is a frequent accompaniment of the disease; it results from severe diarrhoea (and sometimes vomiting).

2.2.5. Marasmic kwashiorkor Children with features of both nutritional marasmus and kwashiorkor are diagnosed as having marasmic kwashiorkor. In the Wellcome classification (see above) this diagnosis is given for a child with severe malnutrition who is found to have both oedema and a weight for age below 60 percent of that expected for his or her age. Children with marasmic kwashiorkor have all the features of nutritional marasmus including severe wasting, lack of subcutaneous fat and poor growth, and in addition to oedema, which is always present, they may also have any of the features of kwashiorkor described above. There may be skin changes including flaky-paint dermatosis, hair changes, mental changes and hepatomegaly. Many of these children have diarrhoea. Laboratory tests Laboratory tests have a limited usefulness for the diagnosis or evaluation of PEM. Some biochemical estimations are used, and give different results for children with kwashiorkor and nutritional marasmus than for normal children or those with moderate PEM. In kwashiorkor there is a reduction in total serum proteins, and especially in the albumin fraction. In nutritional marasmus the reduction is usually much less marked. Often, because of infections, the globulin fraction in the serum is normal or even raised. Serum albumin drops to low or very low levels usually only in clinically evident kwashiorkor. Serum albumin levels are not useful in predicting imminent kwashiorkor development in moderate PEM cases. It is often true that

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the more severe the kwashiorkor, the lower the serum albumin, but serum albumin levels are not useful in evaluating less severe PEM. There is general agreement that serum albumin concentrations below 3 g/dl are low and that those below 2.5 g/dl are seriously deficient (see Table 22). It has also been suggested that serum albumin levels below 2.8 g/dl should be considered deficient and indicate a high risk. TABLE 22 Levels of serum albumin concentrations in malnourished children Concentration Interpretation (g/dl) _ 3.5 3-3.4 2.5-2.9 _ 2.5 Normal Subnormal Low Pathological

Source: Alleyne et al., 1977. Serum albumin determinations are relatively easy and cheap to perform, and unlike the other biochemical tests mentioned below, they can be done in modest laboratories in many developing countries. Levels of two other serum proteins, pre-albumin and serum transferrin, are also of use and not too difficult to determine. Levels of both are reduced in kwashiorkor and may be useful in judging its severity. However, serum transferrin levels are also influenced by iron status, which reduces their usefulness as an indicator of kwashiorkor. Levels of retinol binding protein (RBP), which is the carrier protein for retinol, also tend to be reduced in kwashiorkor and to a lesser degree in nutritional marasmus. However, other diseases, such as liver disease, vitamin A and zinc deficiencies and hyperthyroidism, may also influence RBP levels. Other biochemical tests that have been used or recommended for diagnosing or evaluating PEM have limited usefulness. These include tests for: fasting serum insulin levels, which are elevated in kwashiorkor and low in marasmus; ratio of serum essential amino acids to non-essential amino acids, which is low in kwashiorkor but not much influenced by nutritional marasmus;

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hydroxyproline and creatinine levels in urine, which if low may indicate current growth deficits and nutritional marasmus. These tests are not specific, and most cannot be performed in ordinary hospital laboratories. 2.2.6. Differential diagnosis Nephrosis. Oedema is also a feature of nephrosis, which may therefore be confused with kwashiorkor. In nephrosis, however, the urine contains much albumin as well as casts and cells. In kwashiorkor, there is usually only a trace of albumin. If flakypaint dermatosis or other signs of kwashiorkor are present, the diagnosis is established. Ascites is frequently seen in nephrosis, but only rarely in kwashiorkor. In most developing countries kwashiorkor is a much more common cause of oedema than nephrosis. Severe hookworm anaemia. Oedema may result from this cause alone. In young children kwashiorkor is often also present. In pure hookworm anaemia there are no skin changes other than pallor. In all cases the stools should be examined. Chronic dysentery. In this disease oedema is not a feature. Pellagra. Pellagra is rare in young children. The skin lesions are sometimes similar to those of kwashiorkor, but in pellagra they tend to be on areas exposed to sunlight(not the groin, for example). There may frequently be diarrhoea and weight loss, but no oedema or hair changes. TABLE 2 Comparison of the features of kwashiorkor and marasmus Feature Growth failure Wasting Oedema Hair changes Kwashiorkor Present Present Common Marasmus Present Present, marked Less common

Present (sometimes mild) Absent

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Mental changes Appetite Anaemia Subcutaneous fat Face

Very common Poor Severe (sometimes) Reduced but present May be oedematous

Uncommon Does not occur Good Present, less severe Absent Drawn in, monkey-like Absent

Dermatosis, flaky-paint Common

Fatty infiltration of liver Present

2.2.7. Treatment of severe pem Hospitalization All children with severe kwashiorkor, nutritional marasmus or marasmic kwashiorkor should, if possible, be admitted to hospital with the mother. The child should be given a thorough clinical examination, including careful examination for any infection and a special search for respiratory infection such as pneumonia or tuberculosis. Stool, urine and blood tests (for haemoglobin and malaria parasites) should be performed. The child should be weighed and measured. Often hospital treatment is not possible. In that case the best possible medical treatment available at a health centre, dispensary or other medical facility is necessary. If the child is still being breastfed, breastfeeding should continue. Diet. Treatment is often based on dried skimmed milk (DSM) powder.1 DSM may most simply be reconstituted in hospital by adding one teaspoonful of DSM powder to 25 ml of boiled water and mixing thoroughly. The child should receive 150 ml of this mixture per kilogram of body weight per day, given in six feeds at approximately four-hour intervals. For example, a 5-kg child should receive 5 x 150 ml per day = 750 ml per day, divided into six feeds = 125 ml per feed. Each feed is made by adding five teaspoonfuls of DSM powder to 125 ml of water. There is a risk if non-vitaminized DSM is used. Attention to providing all micronutrients is important. The milk mixture should be fed to the child with a feeding cup or a spoon. If cupor spoon-feeding is difficult - which is possible if the child does not have sufficient appetite and is unable to cooperate or if the child is seriously ill the same mixture is best given through an intragastric tube. The tube should be made of polyethylene; it should be about 50 cm long and should have an internal

38

diameter of 1 mm. It is passed through one nostril into the stomach. The protruding end should be secured to the cheek either with sticky tape or zinc oxide plaster. The tube can safely be left in position for five days. The milk mixture is best given as a continuous drip, as for a transfusion. Alternatively, the mixture can be administered intermittently using a large syringe and a needle that fits the tube. The milk mixture is then given in feeds at four-hour intervals. Before and after each feed, 5 ml of warm, previously boiled water should be injected through the lumen of the tube to prevent blockage. There are better mixtures than plain DSM. They can all be administered in exactly the same way (by spoon, feeding cup or intragastric tube). Most of these mixtures contain a vegetable oil (e.g. sesame, cottonseed), casein (pure milk protein), DSM and sugar. The vegetable oil increases the energy content and energy density of the mixture and appears to be tolerated better than the fat of full cream milk. Casein increases the cost of the mixture, but as it often serves to reduce the length of the hospital stay, the money is well spent. A good and easily remembered formula for the sugar/casein/oil/milk (SCOM) mixture is: one part sugar, one part casein, one part oil and one part DSM, with water added to make 20 parts. A stock of the dry SCOM mixture can be stored for up to one month in a sealed tin. To make a feeding, the desired quantity of the mixture is placed in a measuring jug, and water is added to the correct level. Stirring or, better still, whisking will ensure an even mixture. As with the plain DSM mixture, 150 ml of liquid SCOM mixture should be given per kilogram of body weight per day; a 5kg child should receive 750 ml per day in six 125-ml feeds, each made by adding five teaspoonfuls of SCOM mixture to 125 ml of boiled water. A 30-ml portion of made-up liquid feed provides about 28 kcal, 1 g protein and 12 mg potassium. Rehydration. Children with kwashiorkor or nutritional marasmus who have severe diarrhoea or diarrhoea with vomiting may be dehydrated. Intravenous feeding is not necessary unless the vomiting is severe or the child refuses to take fluids orally. Rehydration should be achieved using standard oral rehydration solution (ORS), as is described for the treatment of diarrhoea (see Chapter 37). For severely malnourished children, unusually dilute ORS often provides some therapeutic advantage. Thus if standard ORS packets are used which are normally added to 1 litre of boiled water, in a serious case a packet might be added to 1.5 litres of water. Treatment of hypothermia. Even in tropical areas temperatures at night often drop markedly in hospital wards and elsewhere. The seriously malnourished child has difficulty maintaining his or her temperature and may easily develop a lower than normal body temperature, termed hypothermia. Untreated hypothermia is a common cause of death in malnourished children. At home the child may have been kept

39

warm sleeping in bed with the mother, or the windows of the house may have been kept closed. In the hospital ward the child may sleep alone, and the staff may keep the windows open. If the child's temperature is below 36C, efforts must be made to warm the child. He or she must be kept in warm clothes and must be kept covered with warm bedding, and there must be an effort to ensure that the room is adequately warm. Sometimes hot-water bottles in the bed are used. The child's temperature should be checked frequently. Medication. Although it is useful to establish standard procedures for treating kwashiorkor and nutritional marasmus in any hospital or other health unit, each case should nevertheless be treated on its own merits. No two children have identical needs. Infections are so common in severely malnourished children that antibiotics are often routinely recommended. Benzyl-penicillin by intramuscular injection, 1 million units per day in divided doses for five days, is often used. Ampicillin, 250 mg in tablet form four times a day by mouth, or amoxycillin, 125 mg three times a day by mouth, can also be given. Gentamycin and chloramphenicol are alternative options but are less often used. In areas where malaria is present an antimalarial is desirable, e.g. half a tablet (125 mg) of chloroquine daily for three days, then half a tablet weekly. In severe cases and when vomiting is present, chloroquine should be given by injection. If anaemia is very severe it should be treated by blood transfusion, which should be followed by ferrous sulphate mixture or tablets given three times daily. If a stool examination reveals the presence of hookworm, roundworm or other intestinal parasites, then an appropriate anthelmintic drug such as albendazole should be given after the general condition of the child has improved. Severely malnourished children not infrequently have tuberculosis and should be examined for it. If the disease is found to be present, specific treatment is needed. Recovery On the above regime, a child with serious kwashiorkor would usually begin to lose oedema during the first three to seven days, with consequent loss in weight. During this period, the diarrhoea should ease or cease, the child should become more cheerful and alert, and skin lesions should begin to clear.

40

When the diarrhoea has stopped, the oedema has disappeared and the appetite has returned, it is desirable to stop tube-feeding if this method has been used. The same SCOM or plain DSM mixture can be continued with a cup and spoon or feeding bowl. A bottle and teat should not be used. If anaemia is still present, the child should now start a course of iron by mouth, and half a tablet (125 mg) of chloroquine should be given weekly. Children with severe nutritional marasmus may consume very high amounts of energy, and weight gain may be quite rapid. However, the length of time needed in hospital or for full recovery may be longer than for children with kwashiorkor. In both conditions, as recovery continues, usually during the second week in hospital, the patient gains weight. While feeding of milk is continued, a mixed diet should gradually be introduced, aimed at providing the energy, protein, minerals and vitamins needed by the child. If the disease is not to recur, it is important that the mother or guardian participate in the feeding at this stage. She must be told what the child is being fed and why. Her cooperation with and follow-up of this regime is much more likely if the hospital diet of the child is based mainly on products that are used at home and that are likely to be available to the family. This is not feasible in every case in a large hospital, but the diet should at least be based on locally available foods. Thus in a maize-eating area, for example, the child would now receive maize gruel with DSM added. For an older child, crushed groundnuts can be added twice a day, or, if preferred by custom, roasted groundnuts can be eaten. A few teaspoonfuls of ripe papaya, mango, orange or other fruit can be given. At one or two meals per day, a small portion of the green vegetable and the beans, fish or meat that the mother eats can be fed to the child, after having been well chopped. Protein-rich foods (e.g. beans, peas, groundnuts, meat, sour milk or eggs) can be given. If eggs are available and custom allows their consumption, an egg can be boiled or scrambled for the child; the mother can watch as it is prepared. Alternatively, a raw egg can be broken into some simmering gruel. Protein-rich foods of animal origin are often relatively expensive. They are not essential; a good mixture of cereals, legumes and vegetables serves just as well. If suitable vitamin-containing foods are not available, then a vitamin mixture should be given, because the DSM and SCOM mixtures are not rich in vitamins. The above maize-based diet is just an example. If the diet of the area is based on rice or wheat, these can be used instead of maize. If the staple food is plantain or cassava, then protein-rich supplements are important. After discharge, or if a moderate case of kwashiorkor has been treated at home and not in the hospital, the child should be followed if possible in the outpatient department or a clinic. It is much better if such cases can visit separately from other patients (i.e. on a particular afternoon or at a child welfare or growth

41

monitoring clinic) to avoid the tumult of most out patient sessions. A relaxed atmosphere is desirable, and the medical attendant should have time to explain matters to the mother and to see that she understands what is expected of her. It is useless just to hand over a bag of milk powder or other supplement, or simply to weigh the child but not provide simple guidance. Satisfactory weight gain is a good measure of progress. At each visit the child should be weighed. Weight is plotted on a chart to provide a picture for the health worker and the mother. Out-patient treatment should be based on the provision of a suitable dietary supplement, but in most cases it is best that this supplement be given as part of the diet. The mother should be shown a teaspoon and told how many teaspoonfuls to give per day based on the child's weight. Many supplements, especially DSM, are best provided by adding them to the child's usual food (such as cereal gruel) rather than by making a separate preparation. The mother should be asked how many times a day she feeds the child. If he or she is fed only at family mealtimes and the family eats only twice a day, then the mother should be told to feed the child two extra times. If facilities exist and it is feasible, the SCOM mixture can be used for outpatient treatment. It is best provided ready mixed in sealed polyethylene bags. 2.2.8. Prognosis deaths in children hospitalized for kwashiorkor or nutritional marasmus occur in the first three days after admission. Case fatality rates depend on many factors including the seriousness of the child's illness at the time of admission and the adequacy of the treatment given. In some societies sick children are taken to hospital very late in the disease, when they are almost moribund. In this situation fatality rates are high. The cause and the severity of the disease determine the prognosis. A child with severe marasmus and lungs grossly damaged by tuberculous infection obviously has poor prospects. The prospects of a child with mild marasmus and no other infection are better. Response to treatment is likely to be slower with marasmus than with kwashiorkor. It is often difficult to know what to do when the child is cured, especially if the child is under one year of age. There may be no mother or she may be ill, or she may have insufficient or no breastmilk. Instruction and nutrition education are vital for the person who will be responsible for the child. If the child has been brought by the father, then some female relative should spend a few days in the hospital before the child is discharged. She should be instructed in feeding with a spoon or cup and told not to feed the child from a bottle unless he or she is under three months of age. The best procedure is usually to provide a thin gruel made

42

from the local staple food plus two teaspoonfuls of DSM (or some other proteinrich supplement) and two teaspoonfuls of oil per kilogram of body weight per day. Instruction regarding other items in the diet must be given if the child is over six months old. The mother or guardian should be advised to attend the hospital or clinic at weekly intervals if the family lives near enough (within about 10 km) or at monthly intervals if the distance is greater. Supplies of a suitable supplement to last for slightly longer than the interval between visits should be given at each visit. It is essential that the diet provide adequate energy and protein. Usually 120 kcal and 3 g of protein per kilogram of body weight per day are sufficient for long-term treatment. Thus a 10-kg child should receive about 1200 kcal and 30 g of protein daily. It should be noted that a marasmic child during the early part of recovery may be capable of consuming and utilizing 150 to 200 kcal and 4 to 5 g of protein per kilogram of body weight per day.

43

CHAPTER III CASE REPORT

Name Age Sex Date of Admission

: DA : 10 years : Male : July, 21th 2013

Main Complaint

: Pallor

History : Pallor happen since one months ago, History of bleeding was not found. Sign of other spontaneous bleeding wasnt found. Patient also complains of fever for about seven days. Fever was remittent and relieved by consumption of anti-pyretic drugs. Patient also complains of cough for about three days. sputum (). Dyspnoe (-). Nausea (+). Vomitting (-). Patient also complaint loss of appetite since 2 months ago. Patient just eating 3-4 tablespoon per meal.Patient admitted of having a significant weight loss in the last two months. Diarrhea(-). Patient also complains of abdomen distention since two months ago. History of blood transfusion was not found. Immunization : complete History of Feeding: 0-6 months of breastfeeding, 6 months-1 years old of breast feeding & soft rice. 1 years of soft rice. History of previous illness: Patient was referral from Rumah Sakit Bandung and diagnosed as anemia History of previous medications: IVFD Ringer Lactate, Ceftriaxone Injection, Ranitidine Injection, Paracetamol Physical Examination Body weight : 12kg Height BW/Age: BH/Age: : 108 cm

44

BW/BH: Presens status Sens. Compos Mentis, Body temperature: 37.1 oC, Pulse: 92 bpm, Respiratory Rate: 30 bpm. Localized status 1. Head : Eye : Light reflexes(+/+), isochoric pupil, conjunctiva palpebra inferior ane (+/+), icteric (-/-) , Ear : Normal appereance ,Mouth : Sianosis (-), Nose: Normal appereance. 2. Neck : Lymph node enlargement (-) 3. Thorax : Symmetrical fusiformis. Epigastrial retraction (-). HR: 92 bpm, reguler, murmur (+) systolic grade III-IV RR: 30 bpm, reguler. Crackles (-/-), interposed rib clearly visible 4. Abdomen: distention (+), symmetrical, Decreased soepel, Peristaltic (+) normal. Hepar: palpable 4cm BAC, blunt edge, flat surface, Pain(-) 5. Extremities : Pulse 90 bpm, regular, adequate pressure and 3. TD: 90/60mmhg, muscle hypotrophy, little volume,warm acral, CRT<

subcutaneous fat left. Beggy pants(+), pitting oedem(-).

45

Laboratory Result: July,21th 2013 Darah Lengkap (CBC) Hemoglobin (HGB) Eritrosit (RBC) Leukosit (WBC) Hematokrit Trombosit (PLT) MCV MCH MCHC RDW Hitung Jenis Neutrofil Limfosit Monosit Eosinofil Basofil Neutrofil Absolut Limfosit Absolut Monosit Absolut Eosinofil Absolut Basofil Absolut Laboratory Result: July, 21th 2013 Homeostasis Function Protombin APTT Trombin 0.91 unit detik value 1.97 Normal value % % % % % 103/L 103/L 103/L 103/L 103/L 59.10 40.10 0.60 0.00 0.200 3.07 2.08 0.03 0.00 0.01 37 80 20 40 28 16 01 2.4 - 7.3 1.7 - 5.1 0.2 - 0.6 0.10 - 0.30 0 - 0.1 g% 106/ mm3 103/ mm3 % 10 / mm fL Pg g% %
3 3

1.30 0.77 5.19 4.80 129 62.30 16.90 27.10 34.30

12.0-14.4 4.75-4.85 4.5- 13.5 36 42 150-450 75-87 25-31 33-35 11.6 14.8

46

METABOLISME KARBOHIDRAT Glukosa ad random GINJAL Ureum Kreatinin ELEKTROLIT Natrium (Na) Kalium (K) Klorida (Cl) mEq/L mEq/L mEq/L 129 4.0 109 135-155 3.6-5.5 96-106 Mg/dl Mg/dl 18.60 0.26 <50 0.50-0.90 Mg/dl 250.50 <200

Differential Diagnosis Thalassemia+ Marasmus type malnutrition

Working Diagnosis Thalassemia + Marasmus type malnutrition Treatment O2 1-2 l/I nasal canule IVFD D5% NacL 0.45% Folic acid 1x5mg , 1x1 mg Inj.Ampicilin 250mg/6 hr/IV Multivitamin without Fe 1Xcth I Vitamin A 200.000 IU Diet F75 110cc/2 hr/oral Transfusion Consult to Respirology department Consult to nutritionand metabolic disease department

47

FOLLOW UP

July, 22 - 25th 2013 S: Pallor O: Sens: CM, Temp: 36.8 oC Head Eye : Light reflexes(+/+), isochoric pupil, pale conjunctiva palpebra inferior (+/+), icteric (-/-) , Ear : Normal appereance ,Mouth : Sianosis (-), Nose: Normal appereance. Thorax Symmetrical fusiformis. Epigastrial retraction (-). HR: 92 bpm, reguler,

murmur (+) systolic grade III-IV RR: 30 bpm, reguler. Crackles (-/-), interposed rib clearly visible Abdomen distention (+), symmetrical, Decreased soepel, Peristaltic (+) normal. Hepar: palpable 4cm BAC, blunt edge, flat surface, Pain(-) Extremities Pulse 90 bpm, regular, adequate pressure and volume,warm acral, CRT< 3. TD: 90/60mmhg, muscle hypotrophy, little subcutaneous fat left. Beggy pants(+), pitting oedem(-).

A: Thalassemia + Marasmus Type Malnutrition+ Moderate Severe Pericardial effusion

P: -

O2 1-2 l/I nasal canule IVFD D5% NacL 0.45% Folic acid 1x5mg , 1x1 mg Inj.Ampicilin 250mg/6 hr/IV Multivitamin without Fe 1Xcth I Vitamin A 200.000 IU Diet F75 110cc/2 hr/oral Inj.furosemid 15mg/12h Spironolacton 2x12.5mg

48

Premed Furosemid 1mg before transfusion

Plan : - Echocardiography - Consult Nutrition and Metabolic disease - Transfusion

Laboratory Result: July, 22th 2013 Homeostasis Function Ferritin (Fe/iron) TIBC unit Hasil menyusul mg/dl g/dl 173 165 51-157 112-346 value Normal value

Hepar Total bilirubin Direct bilirubin ALP AST/SGOT ALT/SGPT mg/dl mg/dl mg/dl U/L U/L 1.20 0.74 37 20 11 <1 0-0.2 <300 <38 <41

Echocardiography Result (25th July 2013) : Moderate-Severe Pericardial Effusion

49

July, 26-29th 2013 S: Dyspnoe (+), Pallor(+) O: Sens: CM, Temp: 36.8 oC, Head Eye : Light reflexes(+/+), isochoric pupil, pale conjunctiva palpebra inferior (+/+), icteric (-/-) , Ear : Normal appereance ,Mouth : Sianosis (-), Nose: Normal appereance. Thorax Symmetrical fusiformis. Epigastrial retraction (-). HR: 92 bpm, reguler, murmur (-)RR: 30 bpm, reguler. Crackles (-/-), interposed rib clearly visible Abdomen distention (+), symmetrical, soepel, Peristaltic (+) normal. Hepar: palpable 4cm BAC, blunt edge, flat surface, Pain(-). Extremities Pulse 90 bpm, regular, adequate pressure and volume,warm acral, CRT< 3. TD: 90/60mmhg, muscle hypotrophy, little subcutaneous fat left. Beggy pants(+), pitting oedem(-). A: Thalassemia + Marasmus Type Malnutrition+ Moderate Severe Pericardial effusion P: O2 1-2 l/I nasal canule IVFD D5% NacL 0.45% Folic acid 1x1mg Inj.Ampicilin 250mg/6 hr/IV Multivitamin without Fe 1Xcth I Diet F75 110cc/2 hr/oral Inj.furosemid 15mg/12h Spironolacton 2x12.5mg Premed Furosemid 1mg before transfusion

Plan: Transfusion

50

July, 30-31th 2013 S: Dyspnoe (+), Pallor(+) O: Sens: CM, Temp: 36.8 oC, Head Eye : Light reflexes(+/+), isochoric pupil, pale conjunctiva palpebra inferior (+/+), icteric (-/-) , Ear : Normal appereance ,Mouth : Sianosis (-), Nose: Normal appereance. Thorax Symmetrical fusiformis. Epigastrial retraction (-). HR: 92 bpm, reguler, murmur (-)RR: 30 bpm, reguler. Crackles (-/-), interposed rib clearly visible Abdomen distention (+), symmetrical, soepel, Peristaltic (+) normal. Hepar: palpable 4cm BAC, blunt edge, flat surface, Pain(-). Extremities Pulse 90 bpm, regular, adequate pressure and volume,warm acral, CRT< 3. TD: 90/60mmhg, muscle hypotrophy, little subcutaneous fat left. Beggy pants(+), pitting oedem(-). A: Thalassemia + Marasmus Type Malnutrition+ Moderate Severe Pericardial effusion P: O2 1-2 l/I nasal canule IVFD D5% NacL 0.45% Folic acid 1x1mg Inj.Ampicilin 250mg/6 hr/IV Multivitamin without Fe 1Xcth I Diet F75 110cc/2 hr/oral Inj.furosemid 15mg/12h Spironolacton 2x12.5mg Premed Furosemid 1mg before transfusion

Plan: Transfusion

51

Laboratory Result: July,31th 2013 Darah Lengkap (CBC) Hemoglobin (HGB) Eritrosit (RBC) Leukosit (WBC) Hematokrit Trombosit (PLT) MCV MCH MCHC RDW Hitung Jenis Neutrofil Limfosit Monosit Eosinofil Basofil Neutrofil Absolut Limfosit Absolut Monosit Absolut Eosinofil Absolut Basofil Absolut GINJAL Ureum Kreatinin Uric Acid Mg/dl Mg/dl Mg/dl 27.70 0.35 3.6 <50 0.50-0.90 <7.0 % % % % % 103/L 103/L 103/L 103/L 103/L 71.50 24.80 2.30 1.40 0.000 3.09 1.07 0.10 0.06 0.00 37 80 20 40 28 16 01 2.4 - 7.3 1.7 - 5.1 0.2 - 0.6 0.10 - 0.30 0 - 0.1 g% 106/ mm3 103/ mm3 % 10 / mm fL Pg g% %
3 3

9.40 2.43 4.32 17.60 37 72.40 25.10 34.70 21.70

12.0-14.4 4.75-4.85 4.5- 13.5 36 42 150-450 75-87 25-31 33-35 11.6 14.8

52

Hepar Total bilirubin Direct bilirubin ALP AST/SGOT ALT/SGPT mg/dl mg/dl mg/dl U/L U/L 1.88 1.46 61 86 33 <1 0-0.2 <300 <38 <41

August 1-3th 2013 S: Dyspnoe (+), Pallor(+) O: Sens: CM, Temp: 37 oC, Head Eye : Light reflexes(+/+), isochoric pupil, pale conjunctiva palpebra inferior (+/+), icteric (-/-) , Ear : Normal appereance ,Mouth : Sianosis (-), Nose: Normal appereance. Thorax Symmetrical fusiformis. Epigastrial retraction (-). HR: 92 bpm, reguler, murmur (-)RR: 30 bpm, reguler. Crackles (-/-), interposed rib clearly visible Abdomen distention (+), symmetrical, soepel, Peristaltic (+) normal. Hepar: palpable 4cm BAC, blunt edge, flat surface, Pain(-). Extremities Pulse 90 bpm, regular, adequate pressure and volume,warm acral, CRT< 3. TD: 90/60mmhg, muscle hypotrophy, little subcutaneous fat left. Beggy pants(+), pitting oedem(-). A: Thalassemia + Marasmus Type Malnutrition+ Moderate Severe Pericardial effusion P: O2 1-2 l/I nasal canule IVFD D5% NacL 0.45% Folic acid 1x1mg Inj.Ampicilin 250mg/6 hr/IV Multivitamin without Fe 1Xcth I Diet F75 110cc/2 hr/oral Inj.furosemid 15mg/12h Spironolacton 2x12.5mg Premed Furosemid 1mg before transfusion

Plan: Transfusion

53

Laboratory Result: August 2, 2013

Darah Lengkap (CBC) Hemoglobin (HGB) Eritrosit (RBC) Leukosit (WBC) Hematokrit Trombosit (PLT) MCV MCH MCHC RDW Hitung Jenis Neutrofil Limfosit Monosit Eosinofil Basofil Neutrofil Absolut Limfosit Absolut Monosit Absolut Eosinofil Absolut Basofil Absolut % % % % % 103/L 103/L 103/L 103/L 103/L 52.00 41.70 4.20 1.30 0.800 1.25 1.00 0.10 0.03 0.02 37 80 20 40 28 16 01 2.4 - 7.3 1.7 - 5.1 0.2 - 0.6 0.10 - 0.30 0 - 0.1 g% 106/ mm3 103/ mm3 % 103/ mm3 fL Pg g% % 7.00 2.68 2.40 20.00 20 74.60 26.10 35.00 21.10 12.0-14.4 4.75-4.85 4.5- 13.5 36 42 150-450 75-87 25-31 33-35 11.6 14.8

54

August 4-6th 2013 S: Seizure(+), Dyspnoe(-) O: Sens:GCS 10( E4M4V2), Temp: 38.2 oC, Head Eye : Light reflexes(+/+), isochoric pupil, pale conjunctiva palpebra inferior (-/-), icteric (-/-) , Ear : Normal appereance ,Mouth : Sianosis (-), Nose: Normal appereance. Neck: Thorax Symmetrical fusiformis. Epigastrial retraction (+). HR: 160 bpm, reguler, murmur (-)RR: 20 bpm, reguler. Crackles (-/-), interposed rib clearly visible Abdomen distention (+), symmetrical, soepel, Peristaltic (+) normal. Hepar: palpable 4cm BAC, blunt edge, flat surface, Pain(-). Extremities Pulse 90 bpm, regular, adequate pressure and volume,warm acral, CRT< 3. TD: 90/60mmhg, muscle hypotrophy, little subcutaneous fat left. Beggy pants(+), pitting oedem(-), reflex physiology(+) Normal, reflex pathology(-) A:Thalassemia + Marasmus Type Malnutrition+ Moderate Severe Pericardial effusion+Central Nervous System Infection (dd: Meningitis,Encephalitis, Meningoencephalitis) P: O2 1-2 l/I nasal canule IVFD D5% NacL 0.225% Folic acid 1x1mg Inj.Ampicilin 500mg/6 hr/IV Inj Ceftriaxone 500mg/12hr IV Multivitamin without Fe 1Xcth I Diet F75 110cc/2 hr/oral Inj.furosemid 15mg/12h Spironolacton 2x12.5mg Premed Furosemid 1mg before transfusion Potassium Correction :KCL 5meQ +20cc D5% finish in 2 hours.(4/8/2013) Acidosis Correction 42meQ(1/2 dose myelon in 200cc D5% finish in 1 hour/240gtt/mikro (5/8/2013) Plan: Transfusion Check AGDA post correction I

55

Laboratory Result: August 4, 2013

Darah Lengkap (CBC) Hemoglobin (HGB) Eritrosit (RBC) Leukosit (WBC) Hematokrit Trombosit (PLT) MCV MCH MCHC RDW Hitung Jenis Neutrofil Limfosit Monosit Eosinofil Basofil Neutrofil Absolut Limfosit Absolut Monosit Absolut Eosinofil Absolut Basofil Absolut % % % % % 103/L 103/L 103/L 103/L 103/L 75.70 16.40 7.00 0.00 0.900 6.84 1.48 0.63 0.00 0.08 37 80 20 40 28 16 01 2.4 - 7.3 1.7 - 5.1 0.2 - 0.6 0.10 - 0.30 0 - 0.1 g% 106/ mm3 103/ mm3 % 103/ mm3 fL Pg g% % 11.40 4.13 9.03 33.20 73 80.40 27.60 34.30 21.30 12.0-14.4 4.75-4.85 4.5- 13.5 36 42 150-450 75-87 25-31 33-35 11.6 14.8

56

Laboratory Result: August,4 2013 AGDA Ph pCO2 pO2 Bikarbonat (HCO3) Total CO2 Kelebihan Basa (BE) Saturasi METABOLISME KARBOHIDRAT Glukosa ad random GINJAL Ureum Kreatinin ELEKTROLIT Natrium (Na) Kalium (K) Klorida (Cl) mEq/L mEq/L mEq/L 135 2.8 106 135-155 3.6-5.5 96-106 Mg/dl Mg/dl 15.00 0.34 <50 0.50-0.90 Mg/dl 362.00 <200 mmHg mmHg mmol/L mmol/L Mmol/L % 7.174 60.8 164.3 21.9 23.7 -6.6 98.6 7.35-7.45 38-42 85-42 22-26 19-25 (-2)-(+2) 95-100

57

Laboratory Result: August,5 2013 AGDA Ph pCO2 pO2 Bikarbonat (HCO3) Total CO2 Kelebihan Basa (BE) Saturasi METABOLISME KARBOHIDRAT Glukosa ad random ELEKTROLIT Natrium (Na) Kalium (K) Klorida (Cl) mEq/L mEq/L mEq/L 145 3.4 164 135-155 3.6-5.5 96-106 Mg/dl 94.1 <200 mmHg mmHg mmol/L mmol/L Mmol/L % 7.27 24 83.5 11.0 11.7 14.2 93.6 7.35-7.45 38-42 85-42 22-26 19-25 (-2)-(+2) 95-100

Laboratory Result: August 6, 2013

Darah Lengkap (CBC) Hemoglobin (HGB) Eritrosit (RBC) Leukosit (WBC) Hematokrit Trombosit (PLT) MCV MCH MCHC g% 106/ mm3 103/ mm3 % 103/ mm3 fL Pg g% 9.80 3.62 4.26 28.60 147 79.00 27.10 34.30 12.0-14.4 4.75-4.85 4.5- 13.5 36 42 150-450 75-87 25-31 33-35

58

RDW Hitung Jenis Neutrofil Limfosit Monosit Eosinofil Basofil Neutrofil Absolut Limfosit Absolut Monosit Absolut Eosinofil Absolut Basofil Absolut

20.60

11.6 14.8 37 80 20 40 28 16 01 2.4 - 7.3 1.7 - 5.1 0.2 - 0.6 0.10 - 0.30 0 - 0.1

% % % % % 10 /L 103/L 103/L 103/L 103/L

51.20 37.60 10.10 0.70 0.200 2.18 1.61 0.43 0.03 0.01

Laboratory Result: August,6 2013 AGDA Ph pCO2 pO2 Bikarbonat (HCO3) Total CO2 Kelebihan Basa (BE) Saturasi mmHg mmHg mmol/L mmol/L Mmol/L % 7.543 37.5 179.3 31.6 32.8 8.5 99.7 7.35-7.45 38-42 85-42 22-26 19-25 (-2)-(+2) 95-100

59

METABOLISME KARBOHIDRAT Glukosa ad random ELEKTROLIT Natrium (Na) Kalium (K) Klorida (Cl) mEq/L mEq/L mEq/L 132 2.4 96 135-155 3.6-5.5 96-106 Mg/dl 138 <200

REFERENCE

http://www.cdc.gov/tb/education/corecurr/pdf/chapter2.pdf Critical care nurse Vol 29, No. 2, APRIL 2009 http://www.aacn.org/wd/cetests/media/c0923.pdf

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http://emedicine.medscape.com/article/230802http://www.cdc.gov/tb/topic/basics/risk.htm http://www.oxfordimmunotec.com/Tuberculosis_International http://www.stoptb.org/wg/dots_expansion/assets/documents/IJTLD_OS_Childhoo dTB_Chapter2.pdf http://www.doh.wa.gov/Portals/1/Documents/Pubs/343-071-WATBManualDiagnosisofTBDisease.pdf