Prolonged Fever in Children: Review of 100 Cases

(1)

Prolonged

Fever

in Children:

Review

of 100

Cases

Philip A. Pizzo, M.D., Frederick H. Lovejoy, Jr., M.D., and David H. Smith, M.D.

From the Department of Medicine, Children ‘s Hospital Medical Center, and the Department of Pediatrics, Harvard Medical School, Boston, Massachusetts

ABSTRACT. One hundred children admitted to a hospital

over a six-year period with temperatures over 38.5 C for longer than two weeks and of undetermined etiology are reviewed. Fifty-two were infectious (21 presumed viral), 20 collagen-inflammatory, 6 malignancy, 10 miscellaneous, and 12 discharged undiagnosed. Children less than 6 years were more likely to have an infectious etiology while 80% of collagen-inflammatory disease occurred in the group older than 6. The overall mortality (9%) was not age-related. Careful history and physical examinations were helpful but the usual laboratory data (CBC, urinalysis, X-ray) 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 common diseases comprised the majority of childhood fevers. Pediatrics, 55:468, 1975, FEVER, FEVER OF UNKNOWN ORIGIN, INFECTIOUS I)ISEASE, COLLAGEN DISEASE, HOSPITALIZEI) CH ILD.

Since Traube1 recommended use of the

ther-mometer for children in 1850, fever has been

appreciated as the single most common chief

com-plaint presented to the physician providing child

health care, accounting for at least 30% of

out-patient 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

been uniform in these studies, the findings have

been similar. Of 1,038 adults reported since

1913,1223 nearly one half were undiagnosed; a

figure

that

has decreased over the past two

dec-ades to 10% to 20%. Infection was the most

fre-quent etiology (29% of total), while

collagen-inflammatory, malignancy, and miscellaneous

diseases each 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 Beeson’9

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 it is

generally presumed that these children have a

serious disease and a poor prognosis, they are often

referred for hospital evaluation, and are generally

(Received July 1; revision accepted for publication October 9, 1974.)

ADDRESS FOR REPRINTS: (PAP) National Institutes

(2)

subjected to a series of costly and sometimes

traumatic diagnostic procedures. Questions as to

the appropriateness of this approach and the

need for guidelines which might circumvent

hos-pitalization and facilitate diagnosis by the

prac-ticing physician was the basis for this study.

MATERIALS AND METHODS

Prolonged fever was defined as a rectal (or its

equivalent) temperature higher than 38.5 C on

more

than

four occasions for at least a two-week

period. Of 800 records of children admitted to

the Children’s Hospital Medical Center from

1966 to 1972 for the evaluation of prolonged fever,

100 met the criteria outlined. Cases were selected

only on the basis of prolonged fever which could

not be explained by the referring physician and

without consideration of the final diagnosis. All

had temperatures higher than 38.5 C, the median

duration was three weeks and more than one half

lasted longer than a month. Data from these

records

were

abstracted, coded, cross-tabulated,

and analyzed by the

x2

technique. Ultimate

diag-nosis was made on the basis of a constellation of

clinical and laboratory findings, except for that of

presumed viral disease which was made from a

consistent clinical course and laboratory findings,

but primarily by the exclusion of other diseases.

Because of the retrospective nature of this study,

specific viral serology and culture was generally

unavailable. Final diagnoses were categorized into

six groups: infectious, presumed viral,

infectious-nonviral, collagen-inflammatory, malignancy,

miscellaneous, and undiagnosed.

Children’s Hospital Medical Center is a general

pediatric hospital that serves as referral center

and primary-care facility, the latter providing

nearly one half of its hospital admissions. Although

70% of the children in this series were referred,

their final diagnosis, mode of evaluation, and

prognosis did not differ from children admitted

from the hospital’s “walk-in” clinics.

RESULTS

Infection caused more than one half the

in-stances of prolonged fever (52), with presumed

viral disorders accounting for 21 cases (Table I).

Collagen-inflammatory disorders accounted for

20 cases, malignant disorders 6, and miscellaneous

causes 10. Twelve children remained

undiag-nosed at the conclusion of their hospitalization.

The 88 children whose prolonged fever was

diag-nosed had one of 35 diseases, only a few of which

could be categorized as unusual.

Six children were less than 6 months of age at

ad-mission; 22 were 6 months to 2 years; 24, 2 to 6

years; 41, 6 to 14 years; and

7,

older than 14 years.

Sixty-five percent were male. Although 91 of the

patients were white, there was no apparent

racial-ly predominant diagnosis. Admissions for

pro-longed fever were most common during the fall

(33) and least common during the summer (17).

Except for the absence of viral disease during

winter, diagnoses had no seasonal dependence.

Certain relationships between diagnosis and

age were noted. Infection was the most common

etiology in all age groups, but 65% of these children

were less than 6 years old (P < .05). The patterns

of infectious diseases were somewhat age-related:

upper respiratory tract infections and viral

syn-dromes were most common in the group aged 6

months to 2 years; endocarditis

and

infectious

mononucleosis occurred only in those older than

6 years; and two children older than 6 years had

chronic streptococcosis. Eighty percent of

chil-dren with collagen-inflammatory diseases were

older than 6 years (P < .05). All children with

inflammatory disease of the bowel were 6 to 14

years of age. Malignancy had no age predilection;

75% of the undiagnosed group were 6 years or

older.

Fever Patterns

and Therapy

Three patterns of fever were observed: (1) daily

spiking (57); (2) relapsing (40); and (3) constant

(3). The height, pattern, or duration did not relate

significantly to diagnosis or severity of illness.

“Toxicity” (a subjective impression of how sick

a child appears to be) was commonly associated

with fever (62), but had no correlation with

diag-nosis or outcome. Prior to admission, 56 of the

patients received some antipyretic (44 records had

no information regarding use). Response to

anti-pyretics yielded no information concerning

diagnosis or outcome but may have contributed

to the “spiking” nature of some fever patterns.

Antibiotics were used in

79

patients prior to

admission, and led to a transient but unmaintained

decrease of fever in 16.

Symptoms

General systemic complaints rarely allowed

differentiation among diagnostic groups.

Ano-rexia, fatigue, and weight loss occurred in over one

half of the patients and one quarter experienced

chills and/or sweats, but none of these symptoms

had diagnostic or prognostic significance.

Head, eye, ear, nose, and throat symptoms were

most common (72 cases). Adenopathy, lower

res-piratory tract symptoms, and abdominal pain

each occurred in one quarter to one half of the

(3)

prog-TABLE I

FINAL DI/GNoSEs 1N 100 PATIENTS

Diagnosis No.

(Tn(!er 6 Years Old (52)

Infectious 34

Viral syndrome 13

Urinary tract infection 3

Bacterial meningitis 3

Pneumonia 3

Tonsillitis 3

Septicemia 2

Sinusitis 2

Generalized herpes simplex 1

Malaria 1

Peritonsillar abscess 1

Osteomyelitis 1

Enteric fever 1

Collagen-inflammatory 4

Rheumatoid arthritis 3

SchOnlein-Henoch purpura 1

Malignancy 4

Leukemia 3

Reticulum cell sarcoma 1

Miscellaneous 7

Central nervous system fever 2

Agranulocytosis 1

Lamellar Icthyosis 1

Milk allergy 1

Aspiration pneumonia 1

Agammaglobulinemia 1

Undiagnosed 3

6 Years and Older (48)

Infectious 18

Viral syndrome 4

Endocarditis 3

Infectious mononucleosis 2

Streptococcosis 2

Osteomyelitis 1

Sinusitis 1

Tonsillitis 1

Tuberculosis 1

Typhoid fever 1

Urinary tract infection 1

Pneumonia 1

Collagen-inflammatory 16

Rheumatoid arthritis 7

Lupus erythematosis 3

Regional enteritis 4

Ulcerative colitis 1

Vasculitis (undefined) 1

Malignancy 2

Lymphosarcoma 1

Leukemia 1

Miscellaneous 3

Beh#{231}et’s syndrome 1

Hepatitis, anicteric 1

Ruptured appendix 1

Undiagnosed 9

nostic significance. Twenty-four patients noted

the presence of cutaneous symptoms (rash,

pm-ritus, 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,

endo-carditis [2], systemic lupus erythematosis [2],

and vasculitis). Six of seven patients with chest

pain, cyanosis, or dyspnea had diseases that

pro-duced either a fatal outcome or serious sequelae

(P <.001). Nine of the 14 children with joint

pains had a collagen disorder (P <.05).

Physical

Signs

Only

27 patients

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

infec-tions, 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 (P <.01)

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

differen-tiate among diagnostic categories nor was it

significantly related to outcome. Cutaneous

findings, significant heart murmur, and

arthro-pathy were findings associated with serious

dis-ease.

Laboratory Studies

More than 90% of patients had a CBC or

un-nalysis 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

prog-nostic correlation. Differential counts were more

helpful.

A

predominance of polymorphonuclear

(4)

collagen-inflammatory disorders (P<.01). Although 75% of

patients with bacterial infections had

polymor-phonuclear predominance, so did 50% with viral

illnesses (including two with a “shift to the left”).

Hematocrit Reading. Forty-one of the

100

pa-tients were anemic for age. Although all children

with a malignancy were anemic (P<.05), low

hematocrit readings did not differentiate among

diagnostic categories.

Urinalysis. Cellular and chemical

abnormali-ties were noted in the urine of 21 patients, but

aided in the final diagnosis in only one of ‘four

children with a urinary tract infection, all three

children with endocarditis, and in five of 20

chil-dren with a collagen-inflammatory disorder.

Ba-cilluria

detected by culture confirmed the

diag-nosis of urinary tract infection in four children.

Erythrocyte Sedimentation Rate (Wintrobe Method). Twenty children had an ESR < 10,

30 children between 10 and 30, and 38 children

> 30. An elevated ESR was found in 75% of

pa-tients with malignancy or collagen-inflammatory

disorders. Of the 20 children with an ESR < 10,

18 had fever secondary to nonserious or viral

disease (P< .05).

Serum Protein Analysis. Reserved

albumin-globulin ratios were found in 34 of the 74 children

tested. Seventy-five percent of those with

col-lagen-inflammatory disorders had such reversals,

compared to 20% with viral disease (P < .05).

An electrophoretic pattern of acute inflammation

(

decreased albumin and increased a1-globulin,

and a2-globulin) was the only type observed in

presumed viral disorders, while 82% (P< .01) of

those with collagen-inflammatory disorders had

decreased albumin and increased a1-globulin,

a2glo’)ul, and y-globulin or decreased albumin,

a1-globulin, and a2-globulin

and

decreased

y-glob-ulin. Because each electrophoretic pattern was

found in all groups, no particular pattern was

di-agnostic.

Radiologic Studies. All children had a chest

x-ray film. Abnormalities were noted in 13 instances.

and were critical for a diagnosis in four children

with pneumonia and in one child with rheumatoid

arthritis and pericarditis. The only diagnostic

intravenous pylograms were in four children with

urinary tract disease. Upper gastrointestinal

tract series and barium enemas were critical to

the diagnosis of four children with regional

enten-tis and one child with ulcerative colitis. Nuclear

scans of the liver (3) were helpful in confirming

the diagnosis in the one child with anicteric

hepa-titis.

Biopsies. Biopsies were performed in 22

pa-tients. Bone marrow examinations

(

14) were

diag-nostic in children with leukemia (4),

lympho-sarcoma, (1) and agranulocytosis (1). They were

of suggestive value in another six cases, revealing

plasma cell predominance in

collagen-inflamma-tory disorders or a “shifted cell line” in infection.

Lymph node biopsies, done in three patients,

revealed a reticulum cell sarcoma in one child and

suggested agammaglobulinemia in another.

Liver biopsies were done in two children, one of

whom was found to have anicteric hepatitis. One

patient had a skin biopsy which revealed lamellar

ichthyosis. Histologic material was thus

diag-nostic in approximately 40% of the cases where

biopsy was performed.

Laparotomy (3), performed because abdominal

signs suggested a surgically correctable lesion or

for diagnostic purposes, revealed an appendiceal

abscess in one and vasculitis in another. One

pa-tient received no diagnositc benefit from this

procedure and, although undiagnosed at

dis-charge, is now clinically well more than a year

later. Two children with chronic tonsillitis were

cured by tonsillectomy.

Studies Most Helpful. The history and/or

phy-sical examination suggested or indicated the final

diagnosis in 62 cases. Serum protein analysis in

conjunction with the sedimentation rate was

use-ful as a screening laboratory test. More specific

studies were related to individual disease

pro-cesses. Bacterial infection was proven by

appro-priate cultures. Histologic examination was

critical in confirming a malignancy whereas serum

protein determinations, specialized serological

studies, and selected radiologic procedures were

important for the diagnosis of

collagen-inflamma-tory disorders. The indications for performing

such procedures were best decided from the

history and physical and screening studies. It is

notable that failure to correctly utilize existing

laboratory data occurred in the evaluation of

one half of the cases, and was the most important

reason for failure to make a diagnosis prior to

hospitalization.

Outcome.

Sixty-two

of the cases in this series

had no lasting sequelae, including all 21 patients

with viral disease and 24 of 31 with bacterial

in-fections. Hence, 88% of the children with an

in-fectious basis for their prolonged fever recovered

completely. As might be expected, this finding

contrasts strikingly to the experience with

child-ren with collagen-inflammatory disorders (90%

of whom had sequelae) and all with malignancies.

There were nine fatalities; malignancy (four),

collagen disorders (two) (systemic lupus

erythema-tosus,

diffuse

vasculitis) and infections (three)

(5)

Undiagnosed Patients. Of the 12 patients

dis-charged 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 a

variety of clinical and laboratory findings. Nearly

all had extensive study, including laporotomy

in two. Six of the nine children, in whom

follow-up was possible, are now clinically well and

asymp-tomatic. Recovery bore no correlation to previous

clinical or laboratory aberrations.

DISCUSSION

It has been presumed by many physicians

that children with prolonged fever generally have

collagen disease or some systemic

process,5

and

therefore have a poor prognosis. The present study

fails to support this thesis: 52% of the children had

an infectious disease; only 20% had a

collagen-inflammatory disorder and more than 60% had no

permanant sequelae.

The diseases causing prolonged fever in

child-ren differed from those reported on adults (Table

I). Children had more viral,

collagen-inflamma-tory,

and miscellaneous causes of fever.

Further-more, the types of disorders represented in the

major disease groups differ between children and

adults: children have more protracted viral and

common infections and less tuberculosis and

occult abscesses. Accordingly, the guidelines

for the evaluation of the child with prolonged

fe-ver cannot be constructed from the voluminous

experience with adults.

Similarly, the value of tissue examination

gleaned from the adult literaturelOhl is less

ap-parent in children. Laparotomy and lymph node

and liver biopsies were rarely performed and were

helpful

only

when abnormalities were found

on physical examination. Bone marrow

examina-tion, however, was a more frequent and

produc-tive procedure, establishing a diagnosis in 40% of

the instances in which it was performed and being

suggestive of a diagnosis in another 40%. This

series suggests, however, that marrow

examina-tion should not be considered a screening test,

but rather utilized with specific clinical or

labo-ratory indications (e.g., elevated ESR, reversed

A/G ratio, or hematologic abnormality).

Establishment of guidelines which might be

utilized by the primary physician in

evaluat-ing the child with prolonged fever with the

possi-bility of circumventing hospitalization was the

goal of this study. The age susceptibility to

dis-ease provides certain general clues. Infections

caused two thirds of the prolonged fever in

chil-dren under 6 years while 80% of the

collagen-in-flammatory

disorders were seen only in the older

group in this series.

Although traditional historical features such

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

re-lated to the cardiovascular system, skin, or joints

ofteii indicated significant pathology and

sug-gested the need for more intense evaluation.

Approximately 80% ofthe children had received

a trial of one or more antibiotics prior to their

admission, but without diagnostic or

therapeu-tic benefit. This suggests that such nonspecific

therapy is unwarranted, and in this series may in

fact have masked the diagnosis in some cases.

The high incidence of infectious processes

em-phasizes the need for bacterial cultures, especially

before antibiotics are started.

Although

we do not advocate their disuse, the

traditional CBC and urinalysis were of relatively

little diagnostic benefit. However, the equally

available sedimentation rate and protein analysis

may be more useful screening procedures. An

ESR > 30, reversed A/G ratio, and

electropho-retic pattern characteristic of chronic

inflamma-tion, though not indicating a specific etiology,

suggested

serious

illness

and

indicated

the

need

for ftirther evaluation. Conversely, a normal

sedimentation rate and A/G ratio in conjunction

with nonspecific clinical findings would suggest

only a need for continued observation. Other

disease-specific laboratory procedures and

con-trast radiographic studies were productive only

when indicated by history or physical signs.

Guidelines for referral or hospitalization of

the child with prolonged unexplained fever

can-not be generalized. Certainly the need for more

sophisticated diagnostic study provides one

instance, but emotional relief for the parents

and pediatrician may be equally important.

Al-though physicians often anticipate unusual causes

for the fever in these children, at least three fourths,

including about 90% for whom an etiologic

diag-nosis could be made, had a disease process

com-monly seen in general pediatrics. The true FUO,

at least as conceived from the adult literature,

would seem to be a rare entity in children. Indeed,

the diagnosis in one haff of these patients could

have been made prior to hospitalization if clinical

and laboratory observations obtained previously

(6)

REFERENCES

1. Traube, L.: Ueber die Wirkungen der Digitalis, in-sbesondere #{252}berden Einfluss derselben auf die KOrper-Temperatur in fieberhaften

Krank-heiten mit einem Anhang flber Temperatur

Messungen bei Kranken. Ann.

Charit#{233}-Kranken-hauses, 1:622, 1850.

2. Pizzo, P. A.: Unpublished data.

3. Sanders, S.: Febrile children in a London practice. Clin. Pediatr., 7:574, 1968.

4. Brewis, E. G.: Undiagnosed fever. Br. Med. J., 1:107, 1965.

5. Bechovitz, A. B., and Moffet, H. L.: Classification of acute febrile illnesses in childhood. Clin. Pediatr., 7:649, 1968.

6. Stokes, J.: Symposium on fever of obscure origin in childhood. Med. Clin. North Am., 3, 1936. 7. Fnlthaler, G. J., and Tilden, T.: Management of

hyper-pyrexia in children. Postgrad. Med., 35:643, 1964. 8. Judge, J. M.: Fever in the pediatric patient. J. Am.

Osteopath. Assoc., 64:1174, 1965.

9. Cone, T. E., Jr.: Diagnosis and treatment: Children with fevers. Pediatrics, 43:290, 1969.

10. Christian, J. R.: Management of the child with fever

of undetermined origin. Nebr. Med. J., 54:379,

1969.

1 1. McClung, J.: Prolonged fever of unknown origin

iii children. Am. J. Dis. Child., 124:544, 1972. 12. Alt, H. L., and Barker, M. H.: Fever of unknown origin.

JAMA, 94:1457, 1930.

13. Kinter, A. R., and Rowntree, L. C.: Long continued low grade idiopathic fever. JAMA, 102:889, 1934.

14. 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.

15. Hamman, L., and Wainwright, C. W.: Diagnosis

of obscure fever: II. The diagnosis of unexplained

high fever. Bull. Johns Hopkins Hosp., 58:307, 1936.

16. Keefer, C. S.: The diagnosis of the causes of obscure fever. Tex. Med., 35:203, 1939.

17. Bottiger, L. E.: Fevers of unknown origin with some remarks on the normal temperature in man. Acta.

Med. Scand., 147:133, 1953.

18. Oppel, T. W., and Bernstein, C. A.: The differential diagnosis of fevers: The present status of the pro-blem of fever of unknown origin. Med. Clin. North Am., 38:891, 1954.

19. Petersdorf, R. G., and Beeson, P. B. : Fever of unexplained origin: Report on 100 cases. Medicine, 40:1, 1961.

20. Geraci, J. E., et a!. : Fever of obscure origin-the value

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21. Sheon, E. P., and Van Ommen, R. A.: Fever of obscure origin. Am. J. Med., 34:486, 1963.

22. Effersoe, P. : Fever of unknown origin: A follow-up study of 34 patients discharged without diagnosis.

Dan. Med. Bull., 15:182, 1971.

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ERRATUM

Cone, T. E., Jr. : Answers to saintly diseases. Pediatrics,

54:683,

1974.

St.

(7)

1975;55;468

Pediatrics

Philip A. Pizzo, Frederick H. Lovejoy, Jr. and David H. Smith