Pyrexia of unknown origin: A microbiological review of cases in pediatric population at a tertiary care hospital

Introduction

Pyrexia of unknown origin (PUO) in children becomes apparent from different infectious causes in both developed and developing countries with limited amount of data from developing countries. Often the cause is an acute infection, which soon becomes evident and responds to treatment, or runs its course. In India, infectious diseases most commonly implicated in children with PUO are salmonellosis, tuberculosis, malaria, rickettsial diseases and atypical prolonged presentations of common viral diseases. Typhoid fever is still a cause of concern due to increasing antibiotic resistance. Its incidence is higher among children under five years of age as compared to adults because children either lack natural immunity or experience high levels of exposure to faecal pathogens. Rickettsial infections are one of the important causes of PUO, but still remain overlooked due to non-specific clinical presentations, low index of suspicion amongst clinicians, limited awareness, and limited diagnostic facilities in developing countries. The incidence of childhood brucellosis is usually under reported and it is ranging between 0.8-1.6%.1

Materials and Methods

The retrospective study was carried out in Department of Microbiology of a Tertiary Care Hospital, enrolling 55 children aged less than or equal to 18 years presenting to the outpatient department with history of fever and in whom no diagnosis could be made after basic investigations and cultures, from September 2018 to December 2018. Out of the numerous cases, children diagnosed with malaria, dengue, leptospirosis and urinary tract infections as cause of fever were excluded from the study. Children fulfilling the inclusion criteria for PUO had temperature of more than or equal to 38°C for more than 21 days without a specific clinical cause. The investigations performed for the diagnosis included Widal test, Weil-Felix test and Brucella test (by Slide and Tube Agglutination method), Salmonella IgM by Immunochromatography method and Blood Culture by BD Bactec 9050 and Bactec FX40 automated system.

Results

During the four months study period, 55 patients with fever, in whom no diagnosis could be made after the basic investigations, were followed up.

Discussion

Children with PUO should be evaluated with epidemiological data, contact history, previous medical history, fever pattern, detailed physical or screening tests to provide adequate information to establish a diagnosis. 2 Prevalence of enteric fever was significant (30.4%) in the age group of 0-21 years as per the study by Bharadwaj et al,3 similar to the results obtained by Govindarajulu et al.1 We got 20% positivity for Salmonella Typhi antibodies by immunochromatography assay, 23.6% positivity in widal slide agglutination test and 21.8% positivity by widal tube agglutination assay. Five patients showed titres for >=160 for Salmonella Typhi O & H antigens, which were presumptively diagnosed and treated as Enteric fever. Definitive diagnosis of enteric fever requires isolation of S. Typhi or S. Paratyphi from blood of patient. However, sensitivity of blood culture is highest in the first week of illness and reduces with advancing illness. Conventionally, a positive widal test result implies demonstration of rising titres in blood or serum samples.4

Agglutinins to the somatic (TO) antigens develop later in the illness and decline slowly and variably in recovery, but those to flagellar antigens (TH) rise early and persist.5 Somatic antigens are widely distributed, hence specificity for Salmonella might be lost. However, widal test is useful for cases in children, who have a low prevalence of pre-existing antibody.6

Serological assays are the simplest diagnostic tests to perform for rickettsial infections. The Weil–Felix test was the first to be used and involves antigens from three Proteus strains: P. vulgaris OX2, P. vulgaris OX19, and P. mirabilis OXK. Its use in the diagnosis of rickettsioses is based on serological cross reactions.7 The test lacks sensitivity and specificity but has historically been used for laboratory diagnosis and provides evidence of newly encountered rickettsioses.

Interpretation of the Weil-Felix test requires knowledge of the disease course and corresponding immune response. A threshold for agglutinins that is considered “normal” is up to 1:40. It is especially seen with Proteus OXK suspensions, in which titers up to 1:160 have been observed in non-infected persons. A positive titer of 1:320 has been observed in 54% of healthy persons and 62% of persons with non-rickettsial infections, giving a low sensitivity with this threshold.8

In our study, only one patient (1.81%) had agglutinins against proteus OX-K antigens but the titre was below 1:80 hence was not held significant. Two patients (3.64%) showed similar titres against Proteus OX2 antigens whereas as many as six patients (10.9%) showed titres below 1:80 against Proteus OX-19 antigen. Four patients (7.25%) showed titres of 1:160 against Proteus OX2 antigens and one patient each showed titres of 1:320 and 1: 640 against the same antigen. However, these patients had no relevant clinical and epidemiological history, hence were not treated for typhus fever. The antibodies appear rapidly during the course of the illness, reach titre of upto 1:5000 by second week and decline rapidly during convalescence.9

Doxycycline is the drug of choice for the treatment of the rickettsioses. It was demonstrated that a single dose cured patients suffering from epidemic typhus and Mediterranean spotted fever. For other rickettsial diseases, a 7–14-day regimen is recommended. For children, doxycycline should also be used. It has been demonstrated that staining of teeth is unlikely to appear when fewer than five therapeutic courses of doxycycline are prescribed in childhood.10

Andriopoulos P. et al, conducted a study wherein 144 cases of brucellosis were identified and treated. Ninety-five percent of the patients had a serological titre >=1:160 with culture-proven brucellosis. 11 A study conducted by Alshaalan et al, reported positive brucella serology test result of >=1:160 using the standard agglutination test (SAT) for patients presenting with symptoms suggestive of brucellosis. For the purpose of screening and in the absence of clinical indicators of active brucellosis, a titre of 1:320 or higher is more specific for the presence of the disease.11, 12 Our study showed presence of one case (1.8%) with Brucella A/M tube agglutination titre of 1: 320.

Conclusion

Definitive dignosis of typhoid fever is made after obtaining growth of Salmonella Typhi or Salmonella Paratyphi A, B or C in blood cultures. Definitive diagnosis of Q fever could be made with growth of Brucella species in blood cultures but isolation may take as long as 14 days. Rickettsia PCR are diagnostic of rickettsial infections. Serological reactions for diagnosis of typhoid fever, rickettsial infections and brucellosis, though indicative of infection, cannot be completely relied on given their low specificity. Also, in the past few decades, new infectious disease etiologies have emerged as an important cause of PUO in developed countries, such as Epstein-Barr virus (EBV), Cytomegalovirus (CMV), Human Immunodeficiency Virus (HIV), Psittacosis, Cat-Scratch disease or Bartonellosis. These are diseases capable of provoking high fever for weeks or months, or even years, without progressing and for which we might not have accurate methods of diagnosis. Definitive diagnosis of chronic infections, however requires culture or molecular testing.

Conflict of Interest

The authors declare no relevant conflicts of interest.

Source of Funding

None.