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Prolonged Fever in Children: Review of 100 Cases Philip A. Pizzo, Frederick H. Lovejoy, Jr. and David H.

Smith Pediatrics 1975;55;468

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 1975 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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From Harvard

of School,

in Children:
H. Lovejoy,Jr.,
Children Massachusetts s Hospital



H. Smith,
and the

of Pediatrics,

A. Pizzo,
the Department

Medicine, Boston,

M.D., and David

Medical Center,


been uniform ABSTRACT. One hundred children admitted to a hospital over a six-year period with temperatures over 38.5 C for been similar. longer than two weeks and of undetermined etiology are 1913,1223 nearly reviewed. Fifty-two were infectious (21 presumed viral), figure that has 20 collagen-inflammatory, 6 malignancy, 10 miscellaneous, to 10% and 12 discharged undiagnosed. Children less than 6 years ades etiology were more likely to have an infectious etiology while 80% of quent collagen-inflammatory disease occurred in the group older inflammatory, than 6. The overall mortality (9%) was not age-related. diseases each
Careful but the history usual and laboratory physical data examinations (CBC, were helpful X-ray) urinalysis,

were notably disappointing; however, sedimentation rates and serum protein electrophoresis were often reliable screening tests. Biopsy and laparotomy were less frequently done but when performed yielded productive information.
Unusual presentations of



comprised 55:468, 1975,






fevers. Pediatrics,



Since Traube1 recommended use of the thermometer for children in 1850, fever has been appreciated as the single most common chief complaint presented to the physician providing child health care, accounting for at least 30% of outpatient visits.2 The etiology and guidelines for the diagnosis of acute febrile illnesses in children have been the subject of several reports.3#{176} In contrast, there has been only one study of the child with fever of more than two weeks in duration.11 Several excellent considerations of adults with prolonged or unexplained fever (FUO) have been published. Although the definition of FUO has not

in these studies, the findings have Of 1,038 adults reported since one half were undiagnosed; a decreased over the past two decto 20%. Infection was the most fre(29% of total), while collagenmalignancy, and miscellaneous caused 5% to 10% of cases. Attempts to quantitate the yield of diagnostic investigations revealed varying findings. Oppel and Bernstein,18 for example, showed that only 92 of 855 laboratory studies were positive, and one half of these were bacteriologic cultures. Petersdorf and Beeson9 pointed to the importance of tissue diagnosis, especially liver biopsy and laparotomy. Sheon and Van Ommen21 observed, however, that biopsy and/or laparotomy were only useful when a patient had fever for more than six months, diffuse adenopathy, or abdominal findings. The lack of such guidelines for children with prolonged fever prompted this review. Since is it generally presumed that these children have a serious disease and a poor prognosis, they are often referred for hospital evaluation, and are generally

(Received 9, 1974.) ADDRESS of Health,



1; revision


for (PAP) 2B54,

publication National Bethesda,

October Institutes Maryland

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REPRINTS: 10, Rooni


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subjected to a series of costly and sometimes years; 41, 6 to 14 years; and , older 7 than 14 years. percent were male. Although 91 of the traumatic diagnostic procedures. Questions as to Sixty-five the appropriateness of this approach and the patients were white, there was no apparent racialdiagnosis. Admissions for proneed for guidelines which might circumvent hos- ly predominant pitalization and facilitate diagnosis by the prac- longed fever were most common during the fall ticing physician was the basis for this study. (33) and least common during the summer (17). Except for the absence of viral disease during MATERIALS AND METHODS winter, diagnoses had no seasonal dependence. Prolonged fever was defined as a rectal (or its Certain relationships between diagnosis and noted. Infection was the most common equivalent) temperature higher than 38.5 C on age were more than four occasions for at least a two-week etiology in all age groups, but 65% of these children less than 6 years old < .05). The (P patterns period. Of 800 records of children admitted towere the Childrens Hospital Medical Center from of infectious diseases were somewhat age-related: 1966 to 1972 for the evaluation of prolonged fever, upper respiratory tract infections and viral syndromes were most common in the group aged 6 100 met the criteria outlined. Cases were selected to 2 years; endocarditis and infectious only on the basis of prolonged fever which could months not be explained by the referring physician and mononucleosis occurred only in those older than without consideration of the final diagnosis. All 6 years; and two children older than 6 years had chronic streptococcosis. Eighty percent of chilhad temperatures higher than 38.5 C, the median with collagen-inflammatory diseases were duration was three weeks and more than one half dren than 6 years (P < .05). All children with lasted longer than a month. Data from these older inflammatory disease of the bowel were 6 to 14 records were abstracted, coded, cross-tabulated, years of age. Malignancy had no age predilection; and analyzed by the x2 technique. Ultimate diagof the undiagnosed group were 6 years or nosis was made on the basis of a constellation of75% clinical and laboratory findings, except for that of older. presumed viral disease which was made from a Fever Patterns and Therapy consistent clinical course and laboratory findings, Three patterns of fever were observed: (1) daily but primarily by the exclusion of other diseases. (57); (2) relapsing (40); and (3) constant Because of the retrospective nature of this study, spiking (3). The height, pattern, or duration did not relate specific viral serology and culture was generally to diagnosis or severity of illness. unavailable. Final diagnoses were categorized into significantly Toxicity (a subjective impression of how sick six groups: infectious, presumed viral, infectiousa child appears to be) was commonly associated nonviral, collagen-inflammatory, malignancy, with fever (62), but had no correlation with diagmiscellaneous, and undiagnosed. nosis or outcome. Prior to admission, 56 of the Childrens Hospital Medical Center is a general received some antipyretic (44 records had pediatric hospital that serves as referral center patients no information regarding use). Response to antiand primary-care facility, the latter providing pyretics yielded no information concerning nearly one half of its hospital admissions. Although diagnosis or outcome but may have contributed 70% of the children in this series were referred, spiking nature of some fever patterns. their final diagnosis, mode of evaluation, and to the Antibiotics were used in9 patients 7 prior to prognosis did not differ from children admitted admission, and led to a transient but unmaintained from the hospitals walk-in clinics. decrease of fever in 16. RESULTS Symptoms Infection caused more than one half the instances of prolonged fever (52), with presumed General systemic complaints rarely allowed viral disorders accounting for 21 cases (Table I). differentiation among diagnostic groups. AnoCollagen-inflammatory disorders accounted for rexia, fatigue, and weight loss occurred in over one 20 cases, malignant disorders 6, and miscellaneous half of the patients and one quarter experienced and/or sweats, but none of these symptoms causes 10. Twelve children remained undiag- chills nosed at the conclusion of their hospitalization. had diagnostic or prognostic significance. Head, eye, ear, nose, and throat symptoms were The 88 children whose prolonged fever was diagcommon (72 cases). Adenopathy, lower resnosed had one of 35 diseases, only a few of which most piratory tract symptoms, and abdominal pain could be categorized as unusual. occurred in one quarter to one half of the Six children were less than 6 months of age at ad- each but were without diagnostic or progmission; 22 were 6 months to 2 years; 24, 2 to 6patients

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( Tn(!er



(52) 34

Viral syndrome Urinary tract infection Bacterial meningitis Pneumonia

Tonsillitis Septicemia Sinusitis

13 3 3 3
3 2 2

nostic significance. Twenty-four patients noted the presence of cutaneous symptoms (rash, pmritus, swelling, infection); these included all patients with a diagnosis of a malignancy (6) and eight of nine of those with an eventual fatal outcome (leukemia [2], lymphosarcoma, endocarditis [2], systemic lupus erythematosis [2], and vasculitis). Six of seven patients with chest pain, cyanosis, or dyspnea had diseases that produced either a fatal outcome or serious sequelae (P <.001). Nine of the 14 children with joint pains had a collagen disorder (P <.05).



Generalized Malaria



1 1

Osteomyelitis Enteric fever Collagen-inflammatory Rheumatoid

SchOnlein-Henoch Malignancy


1 1 4 3
1 4 3

Leukemia Reticulum cell Miscellaneous Central nervous Agranulocytosis

Lamellar Icthyosis

sarcoma system fever

1 7


Milk allergy Aspiration pneumonia Agammaglobulinemia Undiagnosed

1 1 1 3

6 Years Infectious Viral syndrome Endocarditis Infectious mononucleosis Streptococcosis Osteomyelitis Sinusitis


Older (48) 18 4 3 2


Tonsillitis Tuberculosis Typhoid fever Urinary tract infection Pneumonia Collagen-inflammatory Rheumatoid arthritis Lupus erythematosis Regional enteritis Ulcerative colitis
Vasculitis Malignancy (undefined)

1 1 1 1 1 16 7 3 4 1
1 2

had one or more physical findings related directly to their final diagnosis while another 35 had localizing signs that related indirectly to the diagnosis. Children with malignancies, bacterial infections, and miscellaneous disorders more often had focal signs than those with other diseases (P< .01). All patients who died had some localized findings, while only one third with viral infections or without a diagnosis had focal signs. Cutaneous findings on physical examination (rash, infection, pigmentary changes, dehydration) were present in 39 patients, including all who died <.01) (P and in five of six with a malignancy. Significant heart murmurs were found in eight children, four of whom had endocarditis. Of nine patients with joint findings, six had a collagen-inflammatory disorder (P < .05). On the other hand, adenopathy, whether focal or diffuse, was unrelated to diagnosis or outcome. Of 38 patients with findings referable to the abdomen, 26 had hepatomegaly and/or splenomegaly, comprising 70% of abdominal findings. With the exception of children with malignancy, organ enlargement did not differentiate among diagnostic categories nor it was significantly related to outcome. Cutaneous findings, significant heart murmur, and arthropathy were findings associated with serious disease. Laboratory Studies



Lymphosarcoma Leukemia

1 1

Beh#{231}ets syndrome Hepatitis, anicteric Ruptured appendix Undiagnosed

1 1 1 9

More than 90% of patients had a CBC or unnalysis prior to admission. The following results were obtained in our hospital laboratory. Peripheral Blood Cotinti (WBC). Forty-five patients had a normal WBC count, seven less than 5,000/cu mm, 35 between 10,000 and 20,000/cu mm, and 13 more than 20,000/cu mm. The actual WBC was without significant etiologic or prognostic correlation. Differential counts were more helpful. A predominance of polymorphonuclear cells was found in 90% of patients with collagen-


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inflammatory disorders (P<.01). Although 75% of nostic in children with leukemia (4), lymphopatients with bacterial infections had polymorsarcoma, (1) and agranulocytosis (1). They were phonuclear predominance, so did 50% with viral of suggestive value in another six cases, revealing illnesses (including two with a shift to the left). plasma cell predominance in collagen-inflammaHematocrit Reading. Forty-one of the 100 patory disorders or a shifted cell line in infection. tients were anemic for age. Although all children Lymph node biopsies, done in three patients, with a malignancy were anemic (P<.05), low revealed a reticulum cell sarcoma in one child and hematocrit readings did not differentiate among suggested agammaglobulinemia in another. diagnostic categories. Liver biopsies were done in two children, one of whom was found to have anicteric hepatitis. One Urinalysis. Cellular and chemical abnormalities were noted in the urine of 21 patients, but patient had a skin biopsy which revealed lamellar aided in the final diagnosis in only one of four ichthyosis. Histologic material was thus diagin approximately 40% of the cases where children with a urinary tract infection, all three nostic children with endocarditis, and in five of 20 chil- biopsy was performed. dren with a collagen-inflammatory disorder. BaLaparotomy (3), performed because abdominal cilluria detected by culture confirmed the diag- signs suggested a surgically correctable lesion or nosis of urinary tract infection in four children. for diagnostic purposes, revealed an appendiceal Erythrocyte Sedimentation Rate (Wintrobe abscess in one and vasculitis in another. One paMethod). Twenty children had an ESR < 10, tient received no diagnositc benefit from this 30 children between 10 and 30, and 38 children procedure and, although undiagnosed at disis now clinically well more than a year > 30. An elevated ESR was found in 75% of pa- charge, later. Two children with chronic tonsillitis were tients with malignancy or collagen-inflammatory disorders. Of the 20 children with an ESR 10, < cured by tonsillectomy. 18 had fever secondary to nonserious or viral Studies Most Helpful. The history and/or phydisease (P< .05). sical examination suggested or indicated the final Serum Protein Analysis. Reserved albumindiagnosis in 62 cases. Serum protein analysis in globulin ratios were found in 34 of the 74 children conjunction with the sedimentation rate was uselaboratory test. More specific tested. Seventy-five percent of those with col- ful as a screening lagen-inflammatory disorders had such reversals, studies were related to individual disease processes. Bacterial infection was proven by approcompared to 20% with viral disease(P < .05). priate cultures. Histologic examination was An electrophoretic pattern of acute inflammation critical in confirming a malignancy whereas serum (decreased albumin and increased a1-globulin, determinations, specialized serological and a2-globulin) was the only type observed in protein presumed viral disorders, while 82% (P< .01) of studies, and selected radiologic procedures were those with collagen-inflammatory disorders had important for the diagnosis of collagen-inflammadecreased albumin and increased a1-globulin, tory disorders. The indications for performing a2glo)ul, and y-globulin or decreased albumin, such procedures were best decided from the a1-globulin, and a2-globulin and decreased y-globhistory and physical and screening studies. It is ulin. Because each electrophoretic pattern was notable that failure to correctly utilize existing found in all groups, no particular pattern was di- laboratory data occurred in the evaluation of agnostic. one half of the cases, and was the most important Radiologic Studies. All children had a chest x- reason for failure to make a diagnosis prior to ray film. Abnormalities were noted in 13 instances. hospitalization. and were critical for a diagnosis in four children Outcome. Sixty-two of the cases in this series with pneumonia and in one child with rheumatoid had no lasting sequelae, including all 21 patients arthritis and pericarditis. The only diagnostic with viral disease and 24 of 31 with bacterial inintravenous pylograms were in four children with fections. Hence, 88% of the children with an inurinary tract disease. Upper gastrointestinal fectious basis for their prolonged fever recovered tract series and barium enemas were critical to completely. As might be expected, this finding the diagnosis of four children with regional entencontrasts strikingly to the experience with childtis and one child with ulcerative colitis. Nuclear ren with collagen-inflammatory disorders (90% scans of the liver (3) were helpful in confirming of whom had sequelae) and all with malignancies. the diagnosis in the one child with anicteric hepa- There were nine fatalities; malignancy (four), collagen disorders (two) (systemic lupus erythematitis. Biopsies. Biopsies were performed in 22 pa- tosus, diffuse vasculitis) and infections (three) tients. Bone marrow examinations ( 14) were diag(endocarditis [two], septicemia).

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Undiagnosed Patients. Of the 12 patients discharged from the hospital without a diagnosis, follow-up information was obtained in nine cases. Duration after discharge ranged from four months to more than five years. This group presented variety of clinical and laboratory findings. Nearly all had extensive study, including laporotomy in two. Six of the nine children, in whom followup was possible, are now clinically well and asymptomatic. Recovery bore no correlation to previous clinical or laboratory aberrations.

thirds of the prolonged fever in chil6 years while 80% of the collagen-inflammatory disorders were seen only in the older group in this series. traditional historical features such a Although as fever patterns, signs of toxicity, weight loss, chills, and sweats often did not correlate with the severity or type of illness, a careful history and physical examination suggested the diagnosis in 62% of these patients. Signs and symptoms related to the cardiovascular system, skin, or joints ofteii indicated significant pathology and suggested the need for more intense evaluation. DISCUSSION Approximately 80% ofthe children had received a trial of one or more antibiotics prior to their It has been presumed by many physicians but without diagnostic or therapeuthat children with prolonged fever generally have admission, tic benefit. This suggests that such nonspecific collagen disease or some systemic process,5 and is unwarranted, and in this series may in therefore have a poor prognosis. The present study therapy have masked the diagnosis in some cases. fails to support this thesis: 52% of the children had fact The high incidence of infectious processes eman infectious disease; only 20% had a collagenthe need for bacterial cultures, especially inflammatory disorder and more than 60% had no phasizes before antibiotics are started. permanant sequelae. Although we do not advocate their disuse, the The diseases causing prolonged fever in childtraditional CBC and urinalysis were of relatively ren differed from those reported on adults (Table little diagnostic benefit. However, the equally I). Children had more viral, collagen-inflammaavailable sedimentation rate and protein analysis tory, and miscellaneous causes of fever. Furtherbe more useful screening procedures. An more, the types of disorders represented in the may A/G ratio, and electrophomajor disease groups differ between children and ESR > 30, reversed pattern characteristic of chronic inflammaadults: children have more protracted viral and retic though not indicating a specific etiology, common infections and less tuberculosis and tion, suggested serious illness and indicated the need occult abscesses. Accordingly, the guidelines ftirther evaluation. Conversely, a normal for the evaluation of the child with prolonged fe- for sedimentation rate and A/G ratio in conjunction ver cannot be constructed from the voluminous with nonspecific clinical findings would suggest experience with adults. only a need for continued observation. Other Similarly, the value of tissue examination laboratory procedures and congleaned from the adult literaturelOhl is less ap- disease-specific radiographic studies were productive only parent in children. Laparotomy and lymph node trast indicated by history or physical signs. and liver biopsies were rarely performed and were when Guidelines for referral or hospitalization of helpful only when abnormalities were found the child with prolonged unexplained fever canon physical examination. Bone marrow examinanot be generalized. Certainly the need for more tion, however, was a more frequent and producdiagnostic study provides one tive procedure, establishing a diagnosis in 40% of sophisticated instance, but emotional relief for the parents the instances in which it was performed and being pediatrician may be equally important. Alsuggestive of a diagnosis in another 40%. This and though physicians often anticipate unusual causes series suggests, however, that marrow examinain these children, at least three fourths, tion should not be considered a screening test, for the fever about 90% for whom an etiologic diagbut rather utilized with specific clinical or labo- including nosis could be made, had a disease process comratory indications (e.g., elevated ESR, reversed A/G ratio, or hematologic abnormality). monly seen in general pediatrics. The true FUO, Establishment of guidelines which might be at least as conceived from the adult literature, would seem to be a rare entity in children. Indeed, utilized by the primary physician in evaluating the child with prolonged fever with the possi- the diagnosis in one haff of these patients could been made prior to hospitalization if clinical bility of circumventing hospitalization was the have laboratory observations obtained previously goal of this study. The age susceptibility to dis- and had been interpreted accurately. ease provides certain general clues. Infections

caused two dren under


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13. 14.


1 . Traube,

L.: sbesondere heiten



die Wirkungen #{252}ber den Einfluss


der derselben flber


auf Krankdie


A. R., and Rowntree, L. C.: Long continued low grade idiopathic fever. JAMA, 102:889, 1934. Hamman, L., and Wainwright, C. W.: Diagnosis of obscure fever: I. The diagnosis of unexplained, long-continued low grade fever. Bull. Johns
Hopkins Hosp., 58:109, 1936.



bei A.: S.:

Kranken. data. children





2. 3. Pizzo, Sanders, P.

1:622, 1850.
Unpublished Febrile in a London practice.


Clin. 4.

Brewis, 1965.
Bechovitz, acute 7:649,

Pediatr., 7:574, E. G.: Undiagnosed

A. febrile 1968. B., and illnesses

1968. fever.
Moffet, in H. childhood.

Hamman, L., of obscure high fever. 1936. Keefer, C. S.: fever. Tex.
Bottiger, L. E.:

and fever: Bull.

Wainwright, II. The diagnosis Johns Hopkins of the 1939.



W.: Diagnosis of unexplained Hosp., 58:307, of


The diagnosis Med., 35:203,

Fevers of




Med. 1:107, J.,

Classification of Clin. Pediatr.,



the and



in man. A.: origin. The



18. in 19.

Oppel, blem





of the pro-


6. 7.


J. : Symposium
childhood. Med.




Am., 3,






Med. of unexplained


9. 10.


G.J., and Tilden, T.: Management of hyperin children. Postgrad. Med., 35:643, 1964. Judge, J. M.: Fever in the pediatric patient. J. Am. Osteopath. Assoc., 64:1174, 1965. Cone, T. E., Jr.: Diagnosis and treatment: Children with fevers. Pediatrics, 43:290, 1969. Christian, J. R.: Management of the child with fever of undetermined origin. Nebr. Med. 54:379, J., 1969. McClung, J. : Prolonged fever of unknown origin iii children. Am. J. Dis. Child., 124:544, 1972. Alt, H. L., and Barker, M. H.: Fever unknown of origin. JAMA, 94:1457, 1930. Fnlthaler, pyrexia


R. G., and

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ERRATUM Cone, Blaizes T. E., disease Jr. : Answers should be to spelled saintly diseases. Pediatrics, Quinsy.




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Prolonged Fever in Children: Review of 100 Cases Philip A. Pizzo, Frederick H. Lovejoy, Jr. and David H. Smith Pediatrics 1975;55;468
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 1975 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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