Prolonged fever is defined as fever more than

2 weeks duration greater than 38.3◦C (101◦F)

on several occasions. The causes of

prolonged fever are classified in to 4 major

groups:

• infections (most common cause).

• non-infectious inflammatory diseases

(NIID).

• malignancies.

• miscellaneous conditions.

Infection is the most common diagnosis in

most cases of prolonged fever especially in

developing countries which include:

•Bacterial (salmonellosis ,

tuberculosis ,brucellosis, and abdominal or

pelvic abscesses ,osteomyelitis, infective

endocarditis, Pyelonephritis and

tuberculous meningitis ).

•Viral (CMV, EBV, Herpes viruses , and HIV).

•Rickettsial (Q fever).

•Parasitic infections.

• The common infections in Egypt

causing prolonged fever that we will

study in this essay as regard the

diagnosis especially the serology are:

•salmonellosis ,

•tuberculosis(TB) ,

•brucellosis,

•Q fever,

•Epstein-Barr virus (EBV),

•chronic meningitis.

Common infections causing prolonged fever in Egypt

Mal-treated typhoid fever

-Typhoid fever (enteric fever) is caused by the Gram-negative bacterium Salmonella enterica serotype typhi. -Estimates for the year 2000 suggest there are approximately 21.5 million infections and 200,000 deaths from typhoid fever globally each year . -The clinical manifestations of typhoid fever are usually nonspecific, and include prolonged fever and gastrointestinal symptoms.

Typhoid fever in EgyptTyphoid fever in Egypt

-In Bilbeis district (population 664,000) in Lower Egypt the estimated incidence of typhoid fever was calculated to be 13 cases per 100,000 persons per year . -Also the results of population-based surveillance in Fayoum governate indicate that incidence of typhoid fever was 59 cases per 100,000 persons per year.

Brucellosis

-The causative agent is Brucella spp., ( Gram-negative intracellular coccobacillus discovered by David Bruce in 1887). -Brucellosis is a relatively common condition and may present with prolonged fever without a focus, however due its wide spectrum of clinical symptoms it remains an important diagnostic challenge. -It is a zoonotic disease found worldwide, with a high morbidity rate.

BrucellosisBrucellosis in Egypt in Egypt -Brucellosis is endemic in the middle East.

-In Egypt 11% of the population had serological

evidence of infection with Brucella spp., while in

acute febrile illnesses 3% of all bacteraemias were

caused by the organism .

-Although brucellosis is recognized as a common

cause of fever in various parts of Egypt, it is often

misdiagnosed and mistreated.

-More than half of all brucellosis cases were

misdiagnosed as typhoid, and only a quarter of

them received treatment with more than one

antibiotic.

-Tuberculosis is caused by Mycobacterium tuberculosis complex (MTBC). -Tuberculosis may involve every organ in the body but the most common clinical presentation is pulmonary disease. -In 2006, 9.2 million new active disease cases (4.1 million being sputum smear-positive) corresponding to an estimated incidence of 139 per 100,000 population occurred throughout the world. -The highest incidence rate was recorded for the African region , mainly due to high prevalence of HIV infection.

Tuberculosis

Tuberculosis in EgyptTuberculosis in EgyptAccording to a 1997 report from the According to a 1997 report from the

EgyptianEgyptian National Tuberculosis Program, National Tuberculosis Program, revealed that the incidence of smear-revealed that the incidence of smear-positive cases in Egypt is 16 per 100,000 positive cases in Egypt is 16 per 100,000 population, This report concluded that TB population, This report concluded that TB and especially drug-resistant strains of and especially drug-resistant strains of Mycobacterium tuberculosis pose serious Mycobacterium tuberculosis pose serious public health problems and that multiple public health problems and that multiple drug resistance and low cure rates are the drug resistance and low cure rates are the most important problems facing TB control most important problems facing TB control efforts in Egypt .efforts in Egypt .

Qfever Q fever is a widespread zoonotic disease, caused by Coxiella burnetii (C. burnetii). Wild and domestic animals are the reservoir of C. burnetii, It is a zoonosis occurring worldwide. Q fever is associated with a wide spectrum of clinical manifestations. In most cases, this illness has a self-limiting febrile course, but it may also manifest with a variety of non-specific symptoms. As with most other rickettsioses, Q fever is infrequently suspected and remain unrecognized .

Infectious mononucleosis

*The clinical triad of pharyngitis, fever, and lymphadenopathy was first described as “glandular fever,”. *IM is caused by the Epstein Barr virus (EBV), which infects more than 98% of the world’s adult population . *The overall clinical incidence is 45/100 000 and it is particularly common in adolescence. *IM is a clinical syndrome characterized by fever, fatigue, malaise, lymphadenopathy and sore throat.

-Chronic meningitis is defined by persistent

or clinically progressive signs and symptoms

of meningitis, such as headache, fever, stiff

neck, nausea, vomiting, lethargy, and

confusion associated with cerebrospinal fluid

(CSF) changes lasting for a duration of at least

4 weeks without improvement.

Chronic meningitis

-Chronic meningitis is caused by a wide variety of infectious and noninfectious pathogens that remain difficult to diagnose. In Egypt, Tuberculous meningitis (TBM) being one of the most common causes of bacterial meningitis and being associated with a high mortality (47%) and it continues to be a significant public health problem .

Typhoid fever diagnosis Although the mainstay of diagnosing typhoid fever is a positive blood culture it is time-consuming and takes at least 2 to 5 days until the identification of the organism. PCR is a better alternative because it is sensitive and rapid method. PCR-based diagnoses are superior to the classical serological method, Widal test, and blood culture test in terms of their specificity and sensitivity . Nested PCR had higher efficacy in detecting typhoid fever than Widal test, blood and urine cultures .

Isolation of brucella from blood, bone marrow, lymph nodes or cerebrospinal fluids remains the gold-standard for diagnosis of brucellosis in humans. Despite its high specificity, brucella culture has several drawbacks such as slow growth and poor sensitivity. PCR proved to be a very useful tool not only for the diagnosis of acute brucellosis but also as a predictive marker for the course of the disease and the post treatment follow-up, which is valuable for the early detection of relapses .

Brucella diagnosis

Microscopy is still the backbone of Microscopy is still the backbone of laboratory diagnostics in TB.laboratory diagnostics in TB. Many Many nucleic acid amplification methods are much nucleic acid amplification methods are much more sensitive than sputum microscopy, more sensitive than sputum microscopy, and results can be available within several and results can be available within several hours. hours.

The cost and complexity of existing The cost and complexity of existing nucleic acid amplification methods has nucleic acid amplification methods has limited their application in resource-poor limited their application in resource-poor settings. settings.

Transrenal DNA provides a challenging Transrenal DNA provides a challenging new target for molecular tuberculosis new target for molecular tuberculosis diagnosis in all groups of patients. diagnosis in all groups of patients.

Tuberculosis (TB) diagnosis

Q Fever diagnosis

The isolation of the Q fever pathogen is a

reliable diagnostic method, but it remains

time-consuming and hazardous and

requires biosafety. The PCR assays

performed are better tests than pathogen

isolation for the rapid and reliable diagnosis

of Q fever.

Infectious mononucleosis diagnosis

Quantitative Epstein bar virus (EBV) DNA measurement is essential for differentiating the low-level infection of healthy carriers from the high levels characteristic of EBV-related disease. Real-time PCR is the principal technology used for modern EBV viral load measurement.

The identification of meningitis etiology is primarily based on the examination of CSF and other tissues, which includes direct stain, cultures on aerobic, anaerobic media. However, even with the use of modern techniques, the etiology of chronic meningitis remains unknown in a substantial percentage of patients. The CSF polymerase chain reaction (PCR) assay represents a significant advance in the diagnosis of TBM. The results of PCR studies in the CSF have shown a 94—100% specificity but sensitivities ranging from 75% to 100%. CT and MRI are used in the evaluation of TBM and to identify complications.

Chronic meningitis

Maltreated Typhoid fever The most widely used serologic test is the

Widal test, However, false-positive results are common because of antigenic cross sharing with other salmonella serotypes . Several new serologic tests for typhoid fever have been introduced which detect IgM or IgG antibodies to various purified antigens of S. Typhi. The assay methods used include enzyme-linked immunosorbent assay (ELISA), dot-blot ELISA, immunochromatography and a novel particle separation method used in TUBEX. The TUBEX test is simple and rapid to use not only in hospitals but also for outpatients as well. It is good alternative for widal test .

Typhidot-M is a dot enzyme immunoassay for the detection of specific IgM to Salmonella typhi . Typhidot-M was positive in 97% of cases who presented with fever of

<7 days among blood culture positives as compared to Widal, which was positive in

24.2%. It is a dot-Enzyme Immunoassay (EIA), a

new serologic test based upon the presence of specific IgM antibodies to a specific 50 kDa outer membrane protein (OMP) antigen on Salmonella typhi. The test become positive as early as in the first week of the fever, the results can

interpreted visually and available within one hour

Brucellosis Serological testing often is used for the confirmation

of brucellosis. The agglutination tests in tubes, e.g

serum agglutination test (SAT), or on slides (Rose

Bengal) continue to be the mainstay of laboratory

diagnosis . . However, SAT and the other formats of

direct agglutination tests suffer from high false

negative rates in complicated and chronic cases

ELISA is one method that has been incorporated into

serologic diagnosis of brucellosis. Among its

advantages are speed and automatization. ELISA

also allows detection of antibodies against different

bacterial antigenic structures such as corpuscular

antigen, S-LPS or protein antigens .

Tuberculosis

The detection of circulating mycobacterium antigens using specific monoclonal antibodies (mAbs) has been shown to be a promising approach to the detection of active infection. Recently, developed a simple and rapid dot- ELISA test based on IgG monoclonal antibody (TB-55 mAb) specific for a 55-kDa mycobacterial antigen and had been evaluated in the diagnosis of pulmonary as well as extrapulmonary TB .

The gold-standard screening method for LTBI is the tuberculin skin test (TST). The TST has several limitations, including the need for repeat visits and trained staff in addition to limited validity of the results. T-cell–based interferon-γ release assay are whole-blood enzyme-linked immunosorbentassay (ELISA) and enzyme linked immunospot assay(ELISpot). The whole blood ELISA is available commercially as QuantiFERON-TB Gold and an “in-tube” variant, QuantiFERON-TB Gold In-tube . This T-cell-based assay for diagnosing tuberculosis infection gave promising results .

Human Q fever is currently diagnosed by clinical presentation and supporting serological responses against

fixed, whole-cell phase I and phase II forms of the C. burnetii. The serological testing include

immunofluorescence, complement fixation, enzyme- linked immunosorbent assay (ELISA) and microagglutination.Q fever IgG ELISA is a specific alternative method for prevaccination

testing and the diagnosis of Q fever. Worldwide, the most common method used in

human diagnosis of Q fever is the indirect immunofluorescence antibody (IFA).

Q fever

Infectious Infectious mononucleosismononucleosis Detection of IgM antibody against the virus

capsid antigen (VCA) is the best approach for the identification of primary EBV infection. Indirect immunofluorescence assay (IFA) of anti-VCA IgM and IgG antibody has been regarded as the golden standard for the serological diagnosis of EBV infection, and other methods, such as enzyme-linked immunosorbent assays (ELISA) and chemiluminescent immunoassay (CLIA), were developed to improve the assay procedure.

Tuberculous meningitis

Immunological methods such as antibody-capture enzyme-linked immunosorbant assay (ELISA) have been previously used for diagnosing TBM . The cell ELISA method allows further confirmation of the results obtained by antibody-capture ELISA. The presence of a 30-kD protein antigen in CSF of TBM patients indicates that this protein carries the candidate marker antigen which is specific to M. tuberculosis.

Statistical comparisons for cases of typhoid from

2003 to2008 admitted in Mansoura fever hospital

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Statistical comparisons for cases of brucella from 2003 to2008 admitted in Mansoura fever hospital

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2003 2004 2005 2006 2007 2008

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Statistical comparisons for cases of tuberculosis from 2003 to2008 admitted in

Mansoura fever hospital

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2003 2004 2005 2006 2007 2008

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Statistical comparisons for cases of meningitis from 2003 to2008 admitted in Mansoura fever hospital

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2003 2004 2005 2006 2007 2008

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