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Concurrent typhoid fever and dengue hemorrhag ic fever
Abstract Dengue and typhoid fever still remain diseases of major public health importance in the tropics. Individuals in areas endemic for both the diseases are at substantial risk of contracting both these diseases, either concurrently or an acute infection superimposed on a chronic one. In Indonesia as well as in many developing countries both typhoid fever and dengue hemorrhagic fever (DHF) are still endemic and prevalent. In Indonesia the incidence of DHF in 1994 was 9.72/100,000 population with CFR of 2.5% and each year about 640,0001,500,000 cases of typhoid fever were reported with mortality of 1.6-3%. The concurrent infection of both diseases may occur in one patient. Keywords: dengue, typhoid, fever, concurrent
Introduction Typhoid fever is caused by infection of humans with the microorganism Salmonella enterica subspecies enterica serotype Typhi (S. typhi for short). It is a systemic disease characterized by a prolonged fever, malaise and weight loss. On physical examination, characteristic skin lesions, rose spots, usually accompany a hepatosplenomegaly. Without antibiotic treatment the fever may persist for several weeks, and the disease will be fatal in about 15 percent of those affected. The bacterium is transmitted by faecal-oral route, through contaminated water or food.3 S. typhi is highly adapted to its human host; there is no reservoir but man. Therefore, every case of typhoid fever means an infection from a previous one. The immunopathogenesis is characterized by a sustained low-grade bacteremia with microbial invasion of and multiplication within the mononuclear phagocytes lining the sinoids of the liver, spleen, bone marrow, lymph nodes, and Peyer¶s patches. Bacterial multiplication at the latter sites, with necrosis and sloughing of the overlaying mucosal epithelium produces the characteristic ulcerations of Peyer¶s patches in the terminal ileum, a long recognized pathological entity that proved invaluable to distinguish typhoid fever from typhus. Paratyphoid fever is clinically and pathologically a highly similar disease, but caused by Salmonella enterica subspecies enterica serotypes Paratyphi A, B or C (S. paratyphi for short). Enteric fever refers to both typhoid fever and paratyphoid fever.3 Although practically eradicated from the developed Western countries, enteric fever remains a major global health problem due to its high incidence and signi¿cant morbidity and mortality in developing countries. For the year 2000, it
was estimated that 21.650.974 patients contracted typhoid fever, and that 216.510 died due to the disease, whereas paratyphoid fever was responsible for about 25 percent of all enteric fever cases and was estimated to infect 5.412.744 individuals. In Indonesia, the annual costs of treatment of typhoid fever cases has been estimated at approximately US$ 60 million, with an additional US$ 65 million loss of income, and typhoid is cause of deaths of about 20.000 individuals. In Jakarta, clinicians and public health experts believe that typhoid fever still is one of the ¿ve most common febrile illnesses causing the highest mortality among hospitalized patients.3 The clinical presentation of typhoid fever varies from a mild illness with low-grade fever, malaise, and slight dry cough to a severe clinical picture with abdominal discomfort and multiple complications. Many factors influence the severity and overall clinical outcome of the infection. They include the duration of illness before the initiation of appropriate therapy, the choice of antimicrobial treatment, age, the previous exposure or vaccination history, the virulence of the bacterial strain, the quantity of inoculum ingested, host factors (e.g. HLA type, AIDS or other immunosuppression) and whether the individual was taking other medications such as H2 blockers or antacids to diminish gastric acid. Patients who are infected with HIV are at significantly increased risk of clinical infection with S. typhi and S. paratyphi. Evidence of Helicobacter pylori infection also represents an increased risk of acquiring typhoid fever.4 Acute typhoid fever is characterized by prolonged fever, disturbances of bowel function (constipation in adults, diarrhea in children), headache, malaise and anorexia. Bronchitic cough is common in the early stage of the illness. During the period of fever, up to 25% of patients show exanthem (rose spots), on the chest, abdomen and back.4 Acute typhoid fever may be severe. Depending on the clinical setting and the quality of available medical care, up to 10% of typhoid patients may develop serious complications. Since the gut-associated lymphoid tissue exhibits prominent pathology, the presence of occult blood is a common finding in the stool of 10-20% of patients, and up to 3% may have melena. Intestinal perforation has also been reported in up to 3% of hospitalized cases. Abdominal discomfort develops and increases. It is often restricted to the right lower quadrant but may be diffuse. The symptoms and signs of intestinal perforation and peritonitis sometimes follow, accompanied by a sudden rise in pulse rate, hypotension, marked abdominal tenderness, rebound tenderness and guarding, and subsequent abdominal rigidity. A rising white blood cell count with a left shift and free air on abdominal radiographs are usually seen.4 Dengue fever (DF) is an acute febrile viral disease frequently presenting with headaches, bone or joint and muscular pains, rash and leukopenia as symptoms. Dengue haemorrhagic fever (DHF) is characterized by four major clinical manifestations: high fever, haemorrhagic phenomena, often with hepatomegaly and, in severe cases, signs of circulatory failure. Such patients may develop hypovolaemic shock resulting from plasma leakage. This is called dengue shock syndrome (DSS) and can be fatal.5
Dengue viruses are transmitted to humans through the bite of infected Aedes mosquitos, principally Aedes aegypti, and are therefore considered to be arboviruses (arthropod-borne viruses). Once infected, a mosquito remains infected for life, transmitting the virus to susceptible individuals during probing and feeding. Infected female mosquitos may also pass the virus to the next generation of mosquitos by transovarian transmission, but this occurs infrequently and probably does not contribute signi¿cantly to human transmission. Humans are the main amplifying host of the virus, although studies have shown that monkeys in some parts of the world may become infected and perhaps serve as a source of virus for feeding mosquitos. The virus circulates in the blood of infected humans at approximately the time that they have fever, and uninfected mosquitos may acquire the virus if they feed on an individual when he or she is viraemic. The virus then develops in the mosquito for a period of 8±10 days before it can be transmitted to other humans during subsequent probing or feeding. The length of time required for this extrinsic incubation depends in part on environmental conditions, especially ambient temperature.5 Patients with a dual infection were those with both DHF or DSS and concurrent bacteremia. Concurrent bacteremia was defined as a positive bacterial culture of blood sampled from a patient less than 72 hours after he or she was hospitalized for DHF or DSS. Elderly individuals with a dengue virus infection are more likely to develop a critical condition, and were at risk for acquisition of bacterial coinfections, but not for concurrent bacteremia. Prolonged fever and acute renal failure were independent predictive factors for dual infection.6 Yao Lei et al have reported that an abnormal immune status in dengue patients during a dengue serotype 3 Taiwan outbreak in 1998. Analysis of the clinical blood cell count showed that increase of immature neutrophils developed at fever day 5-6, CD4 dim or CD8 dim monocytosis at day 6-7 and atypical lymphocytosis at day 8-10 post fever onset. The PHA stimulated T cell response was depressed as well. These changes in immune parameters are indicative of aberrant immune activation during dengue virus infection and might be involved in the initiation of the dengue pathogenesis. Dengue-infected patients usually are leukopenic for several days during the acute infection, characterized by a decrease in the absolute number of neutrophils and monocytes.7 Because of the possible overlapping clinical manifestations of infections, concurrent bacteremia is easily overlooked in a dengue endemic setting. Failure to make a timely diagnosis of dual infection and starting early additional antibiotic therapy accordingly will put the affected patients in jeopardy. To avoid otherwise preventable mortality and morbidity, clinicians should be alert to the potential for a concurrent bacteremia when facing a patient with DHF with a prolonged fever (>5 days) and therefore initiate a timely additional antimicrobial treatment until blood cultures are negative.6
Table.1 Differential diagnosis of dengue fever8
Case report A 19-year-old girl was admitted to Ulin Hospital on 10 January 2010. She was sent from Cempaka Local Government Clinic, Banjarbaru with diagnosis Typhoid fever and DHF. She complained of fever more than 1 week, headache, nausea, anorexia and myalgia. Her first trombosit test from Banjarbaru is 90.900/ul, anemia, leucopenia, prolonged BSR, and positive Widal test. On admission at the Ulin Hospital, the patient¶s blood pressure was 120/80 mmHg; heart rate 80 beats per minute; body temperature, 36,0 oC; and respiratory rate, 20 breaths per minute. On physical examination, she was conscious, GCS 45-6, with anemic conjunctival, no filthy tongue and epigastrium tenderness on mild palpation. There is no haematemesis, gingival bleeding and melena, but she has maculopapular rash over her bilateral upper extremity from a few days before. She has no history of jaundice, no hepatosplenomegaly and no edema in upper or lower extremity. She has no history to take a vacation recently.
Test HAEMATOLOGY Haemoglobin Leucocyte Haematocryte Trombocyte BSR Diff. Count Basophil % Eosinophil % Stab % Segment % Lymphocyte % Monocyte %
11,23 3.38 35 90.9 21 0 1 2 55 40 2
12.0 ± 16.0 4,0 ± 10,5 35 ± 45 150 ± 450 <15 0.0-1.0 1.0-3.0 2.0-5.0 50.0-70.0 25.0-40.0 2.0-6.0
g/dL thousand/ul Vol% thousand/ul mm/hour % % % % % %
Table 2. Laboratory test in Banjarbaru (9 January 2010)
Widal Test 1/40 1/80 1/160 1/320 1/640 Serology Test Dengue
Salmonella typhi (O) Positive Positive Positive Positive Negative
Salmonella typhi (H) Positive Positive Positive Negative Negative
Salmonella paratyphi (A) Positive Positive Negative
Salmonella paratyphi (B) Positive Positive Negative
Table.3 Laboratory confirmatory test results in Banjarbaru (9 January 2010).
Test HAEMATOLOGY Haemoglobin Leucocyte Erythrocyte Haematocryte Trombocyte RDW-CV MCV.MCH.MCHC MCV MCH MCHC Diff. Count Neutrophil % Lymphocyte % MID % Neutrophil # Lymphocyte # MID#
11,4 3 4,62 35 72 15,5 76 24,7 32,5 22,7 59,1 12,4 0,69 1,79 0,8
12.0 ± 16.0 4,0 ± 10,5 3.90 ± 5.50 35 ± 45 150 ± 450 11.5 ± 14.7 80.0 ± 97.0 27.0 ± 32.0 32.0 ± 38.0 50.0 ± 70.0 25.0 ± 40.0 3.0-9.0 2.50 ± 7.00 1.25 ± 4.00 0.30-1.00
g/dL thousand/ul billion/ul Vol% thousand/ul % Fl Pg % % % % thousand/ul thousand/ul thousand/ul
Table.4 Laboratory test results on admission (10 January 2010). Laboratory test showed haemoglobin amount is 11,7 g/dl, therefore transfusion of PRC is not necessary to do. Thrombocyte count is 72.000/ul but the only bleeding manifestation is from petechiae in tourniquet test. Furthermore there is no reason to give her TC transfusion. For control of the disease, on day 1st of admission she was given injection of ranitidine 40mg twice a day, injection methylprednisolone 125mg twice a day, antrain injection twice a day if necessary. For oral medication she has cholescor 3 times a day. On day 2nd, the oral drug added with of ciprofloxacin 500mg, 2 times/day, and methylprednisolone injection was tapered once a day. On day 3rd , all of injection stopped, and the oral drugs added with imunos tablet once a day. On day 1st until day 3rd of admission the patient¶s blood pressure, heart rate, respiratory and body temperature rate were in normal level. Her complaine of fever, pain and headache has decreased. The patient was being discharged 3 days after admission in stable condition and decreased of complain. The doctor was planned to give cholescor 3 times a day, imunos once a day, ciprofloxacin twice a day and also regular checkup one week after home. Discussion She has diagnosed with DHF grade II and Typhoid fever. We diagnosed her with DHF grade II because her complained prior to admission was mild to high fever more than 1 week, headache, myalgia, then in 5th day of fever she has petechiae at her bilateral upper extremity. Her laboratory findings show leucopenia and thrombocytopenia, prolonged BSR, but her dengue serology test
was negative. At her 2nd care day, she has more hemorrhagic manifestation, in her case was melena. Clinical manifestation of dengue hemorrhagic fever is acute febrile illness of 2-7 days duration with 2 or more of the following manifestations: headache, retro-orbital pain, myalgia, arthralgia, rash, hemorrhagic manifestations, leucopaenia. Infants and persons under 15 may have a nonspecific febrile illness with maculopapular rash. Older patients may have a mild febrile syndrome or the classical incapacitating disease.4 Laboratory criteria for confirmation of dengue infection; One or more of the following:4 1. Isolation of the dengue virus from serum, plasma, leukocytes, or autopsy samples 2. Demonstration of a 4-fold or greater change in reciprocal IgG or IgM antibody titres to one or more dengue virus antigens in paired serum samples 3. Demonstration of dengue virus antigen in autopsy tissue, serum or CSF samples (immunohistochemistry or immunofluorescence or ELISA) 4. Detection of viral genomic sequences in autopsy tissue, serum or CSF samples by polymerase chain reaction (PCR). The WHO definition for dengue haemorrhagic fever is:4 1. Fever or history of recent fever lasting 2-7 days 2. Thrombocytopaenia of 100 000 platelets or less per cc In practice, average of 3 platelets or less per oil-immersion field averaged on 10 fields 3. At least one of the following haemorrhagic manifestations: positive tourniquet test, petechiae/ ecchymoses/ purpura, haematemesis/ melena, other overt bleeding. 4. At least one of the following manifestations of plasma leakage due to increased vascular permeability: >20% rise in average haematocrit for age and sex, >20% drop in haematocrit following volume replacement, pleural effusions/ ascites/ hypoproteinaemia.
Table 5. WHO grading of severity of dengue fever
She also has undocumented remitten fever 2 weeks prior to admission, abdominal pain, and short episode of diarrhea. On admission she complained of nausea, anorexia, and epigastrium tenderness. The Widal test showed raised in T(O) and T(H) titres of 1:320 and 1:160, P(A) and P(B) titres of 1:80 and 1:80. The definitive diagnosis of typhoid fever requires the isolation of Salmonella enterica serotype Typhi from the patient. Cultures of blood, stool, urine, rose spots, blood mononuclear cell-platelet fraction, bone marrow, and gastric and intestinal secretions can all be useful for diagnosis. However, this requires laboratory equipment and technical training that are beyond the means of most primary health care facilities in the developing world. Consequently, Widal test is the only specific diagnostic investigation available in most tropical regions. The Widal test which is readily available and inexpensive was introduced as a serologic technique to aid in diagnosis of typhoid fever and has been used for more than a century.3,9 The test was based on demonstrating the presence of agglutinin (antibody) in the serum of an infected patient, against the H (flagellar) and O (somatic) antigens of Salmonella typhi. The role of the Widal test had been to increase the index of suspicion for the presence of typhoid fever by demonstrating a positive agglutination during the acute and convalescent period of infection with evidence of a four-fold rise of antibody titre. The Widal test reaction involves the use of bacterial suspensions of S. typhi and S. paratyphi µA¶ and µB¶, treated to retain only the µO¶ and µH¶ antigens. These antigens are employed to detect corresponding antibodies in the serum of a patient suspected of having typhoid fever. The IgM somatic O antibody appears first and represents the initial serologic response in acute typhoid fever, while the IgG flagella H antibody usually develops more slowly but persists for longer. Two types of agglutination techniques are available: the slide test and the tube test.3,9 Several studies frequently showed the occurrence of typhoid secondary DHF. They also studied the mechanism, included potential risk for a concurrent bacteremia when facing a patient with DHF with a prolonged fever (>5 days), but still a little studies concerned to DHF secondary typhoid. In this case we assumed that she has typhoid first then DHF, because the first clinical manifestation was typical for typhoid and her Widal test was positive. Diagnosis of DHF established because she was a resident in Banjarbaru, where recently occur DHF epidemic, and her clinical manifestation support the diagnosis. On day 1 of admission she was started on ranitidine injection 40mg twice a day, methylprednisolone injection 125mg twice a day and antrain injection twice a day if necessary. For oral medication she has cholescor 3 times a day. On day 2nd, the oral drug added with of ciprofloxacin 500mg, 2 times/day, and methylprednisolone injection was tapered once a day. On day 3rd , all of injection stopped, and the oral drugs added with imunos tablet once a day. Ranitidine belongs to the class of H2-receptor antagonists. Used in the treatment of peptic ulcer and gastro-oesophageal reflux disease (GERD). Ranitidine inhibits stomach acid production.10 Methylprednisolone is in a class of drugs called steroids. It prevents the release of substances in the body that cause inflammation. Methylprednisolone is
used to treat many different conditions such as allergic disorders, skin conditions, ulcerative colitis, arthritis, lupus, psoriasis, or breathing disorders.11 Antrain contents metamizole sodium, belongs to the class of pyrazolone preparations. Used to relieve pain especially colic and post-operate and fever. Antrain dosage in tablet is 1 tablet 6-8 hour, maximal 4 tablets daily and in ampul 500 mg every 6-8 hour IM/IV, maximal 3 times daily.12 Ciprofloxacin belongs to the class of quinolones, fluoroquinolone. Used in the treatment of systemic infections. Broad spectrum antibiotics were given to cover the possibility of septicemia. Cholescor contents Monascus purpureus Went. Cholescor helps in the maintenance of health and in the reduction of LDL, total-cholesterol and triglyceride levels in borderline conditions. Cholescor have side effect which raised thrombocyte amount, so in this case, we used cholescor dominantly for its raised thrombocyte amount function.13,14 Imunos contents Echinacea (EFLA 894) 500 mg, zinc picolinate 10 mg, selenium 15 mcg and ascorbic acid 50 mg. Used for nutritional supplement to stimulate the immune system during acute and chronic respiratory tract infection; adjuvant therapy in acute and chronic infection.15 Conclusion The mechanism typhoid secondary DHF fever is being studied, but still no research result for the mechanism DHF secondary typhoid. In this case we assumed that she has typhoid fever first then DHF. The small number of concurrent bacteremia with viremia shall not overlooked our diagnosis. Clinicians should be alert to a concurrent probability. References 1. Uneke CJ. Concurrent malaria and typhoid fever in the tropics: the diagnostic challenges and public health implications. J Vector Borne Dis 2008;45:133142. Sudjana P, Jusuf H. Concurrent dengue hemorrhagic fever and typhoid fever infection in adult: case report. Southeast Asian J Trop Med Public Health 1998;29:370-372. (Abstract) Ali S. Typhoid fever: aspects of environment, host and pathogen interaction. Hollandse Hoogte, Jakarta 2006. -----. WHO recommended strategies for the prevention and control of communicable disease. WHO 2001. -----. Dengue haemorrhagic fever: diagnosis, treatment, prevention and control. WHO Genewa second edition 1997. Lee IK, Liu JW, Yang KD. Clinical characteristics and risk factor for concurrent bacteremia in adult with dengue hemorrhagic fever. Am J Trop Med Hyg 2005;72:221-226. Lei HY et all. Immunopathogenesis of dengue hemorrhagic fever. Am J Infect Dis 2008;4:1-9.
3. 4. 5. 6.
Cunha BA, Johnson D, Brian M. Atypical dengue fever mimicking typhoid fever in college student traveler. Am J Med 2009;122:1-3. -----. Background document: the diagnosis, treatment and prevention of typhoid fever. WHO 2003.
10. -----. Ranitidine. Available from URL: www.mims.com (download at February 5th 2010) 11. -----. Methylprednisolone. Available from URL: www.drugs.com (download at February 5th 2010) 12. -----. Antrain. Available from URL: www.mims.com (download at February 5th 2010) 13. -----. Ciprofloxacine. Available from URL: www.mims.com (download at February 5th 2010) 14. -----. Cholescor. Available from URL: www.mims.com (download at February 5th 2010) 15. -----. Imunos. Available from URL: www.mims.com (download at February 5th 2010)