Prolonged Fever, Diarrhea, Abdominal Pain, and Joint Pain in a 9-Year- Old Boy

A 9-year-old African American boy with no significant past medical history was admitted directly from his primary care physician’s office to our inpatient unit with a 12-day history of fever, abdominal pain, and diarrhea, and a 1-day history of joint pain. He had high-grade fevers (maximum temperature of 104°F) that were responsive to antipyretics. Abdominal pain was generalized, continuous, and mild to moderate in severity, with no aggravating or relieving factors. He had 2 to 3 episodes of nonbloody, nonmucousy, watery stool daily. He denied nasal congestion, cough, sore throat, emesis, headache, chest pain, dysuria, or rash. There was no history of travel or contact with animals. His family history was significant for rheumatoid arthritis in the maternal grandmother.

During the 12 days of fever, he was seen 3 times (day 2, day 5, and day 7 of symptoms) in the emergency department (ED), during which he had a normal physical examination and was diagnosed with a viral illness. A complete blood count (CBC) and C-reactive protein obtained during these visits were normal. He was seen by his primary care physician on day 13, when he developed additional symptoms of right first interphalangeal joint, right elbow, right wrist, and left knee pain.

Fever is 1 of the most common complaints in pediatrics and is the reason for approximately one-third of all outpatient and ED visits.^1,2  Most of the children with fever have a self-limiting viral illness; however, prolonged fever can be an indicator of major illness. Our patient presented with prolonged fever and abdominal pain; appendicitis, intraabdominal abscess, hepatitis, pancreatitis, cholecystitis, pyelonephritis, and inflammatory bowel disease should all be ruled out. Infections are often at the top of the differential diagnosis list because they are common identifiable causes of prolonged fever.^3,4  With 12 days of fever, abdominal pain, and diarrhea, bacterial and parasitic causes of diarrhea (Salmonella, Shigella, Campylobacter, Yersinia, and Clostridium difficile) should be considered. In addition, given the new history of joint pains, reactive arthritis should be considered.

Infections are a primary consideration for febrile illness and are a cause of prolonged fever 16% to 79%^5,6  of the time. Aside from a viral illness like infectious mononucleosis, bacterial infections like enteric fever, tuberculosis, bartonellosis,⁷  and brucellosis should also be considered. Liver abscesses, hepatitis, spinal infections, and pyelonephritis are also important to consider in a patient with prolonged fevers and abdominal symptoms. With the joint pains, it is pertinent to obtain a history of travel to areas endemic to Lyme disease. Lastly, Kawasaki disease (KD) needs to be considered and has been described in the literature in this age group as case reports.⁸ 

The patient’s vital signs on arrival to the floor were a heart rate of 114 beats per minute, temperature of 102°F, blood pressure (BP) of 130/97 mm Hg, a respiratory rate of 40 breaths per minute, and oxygen saturation of 99% on room air. He was at the fifth and 30th percentile for his height and weight, respectively. Physical examination revealed an alert but tired-appearing boy. Respiratory examination revealed good air entry in all lung fields with no added sounds and no retractions or nasal flaring. Abdominal examination was normal. Positive physical findings included grade II soft systolic murmur best heard on the left upper sternal border and a small (<1 cm) nontender, mobile cervical lymph node in the anterior triangle of the neck. There was mild pain and swelling of the right elbow. Repeat vital signs after antipyretic revealed a heart rate of 80 beats per minute, temperature of 97.5°F, BP of 117/72, respirations of 24 breaths per minute, and oxygen saturation of 100% on room air.

A normal abdominal examination excludes causes like appendicitis, intraabdominal abscess, cholecystitis, and pancreatitis. According to the criteria,⁹  the diagnosis of KD requires the presence of fever lasting ≥5 days, combined with at least 4 of the 5 physical findings: nonexudative conjunctivitis, mucositis, rash, extremity changes, and cervical lymphadenopathy (>1.5 cm in diameter). Our patient did not meet these criteria; hence, KD was excluded. The presence of arthritis suggests an inflammatory and/or autoimmune process. The presence of a heart murmur and fever raises concerns about cardiac causes like infective endocarditis and rheumatic fever.

Acute rheumatic fever and infective endocarditis are high on the differential with these findings. As per modified Jones criteria,¹⁰  the patient needs 2 major or 1 major plus 2 minor criteria along with evidence of a preceding group A Streptococcus (GAS) infection to meet the diagnosis of acute rheumatic fever. He has arthritis and fever, which fulfills 1 major and 1 minor criterion. The patient will need laboratories to verify the history of preceding streptococcal infection, elevated or rising antistreptolysin O (ASO) titer, other antistreptococcal antibody, or a positive throat culture result or a positive rapid antigen test result. The patient does not have risk factors or clinical findings (except heart murmur) for infective endocarditis as per modified Duke criteria,¹¹  but a negative blood culture result is needed. An echocardiogram is required to rule out both acute rheumatic fever and infective endocarditis. Lyme disease is also on the differential but is less likely given the lack of travel history to endemic areas like northeast or upper Midwestern United States.

There is no standardized definition for fever of unknown origin (FUO). For clinical purposes, it is defined as fever >38.3°C (101°F) at least once per day for ≥8 days with no apparent diagnosis after initial outpatient or hospital evaluation that includes a detailed history, thorough physical examination, and initial laboratory assessment.^4,12  Most of these patients will have some type of workup done, although it is not a definite prerequisite.¹³  Our patient meets the clinical definition of FUO.

Clinicians often get confused about FUO and fever without a source. Fever without a source may need workup including laboratories and imaging and may progress to FUO if still no cause is found after 1 week of fever.

Diagnostic evaluation was initiated with CBC, comprehensive metabolic panel, magnesium, phosphorus, lipase, fecal calprotectin, gastrointestinal (GI) FilmArray (a qualitative multiplex polymerase chain reaction test),¹⁴  stool for occult blood, and urinalysis. CBC revealed hemoglobin (Hb) of 10.8 g/dL down from 12.5 g/dL obtained 7 days ago in the ED, but the rest of the CBC and other tests were normal (see Table 1). Radiographs of the chest and right upper extremity were normal. Erythrocyte sedimentation rate (ESR) was elevated at 70 mm, and ASO titer was elevated at 281 IU/mL (normal range <200 IU/mL). Blood and urine culture results were negative. An abdominal computed tomographic scan and echocardiogram were normal.

The patient’s diarrhea and abdominal pain resolved within 24 hours, but he continued with fever and intermittent joint pains affecting the bilateral wrists, ankle, and elbow and knee joints. Concurrently, he also developed dull aching lower back pain. Radiograph of the spine was normal. He was treated symptomatically with oral acetaminophen and ibuprofen.

Negative blood culture results and normal echocardiogram rule out infective endocarditis. Similarly, resolving abdominal pain and diarrhea with negative GI FilmArray results makes bacterial causes of gastroenteritis less likely. The patient has polyarthritis, fever, and elevated ESR with single elevated ASO titer. In the absence of convalescent titer or a positive throat culture result, this cannot be considered as recent evidence of GAS infection. ASO titers can stay elevated for months after GAS infection and so may not confirm recent infection in the last 3 weeks.¹⁵ 

A normal radiograph does not rule out osteomyelitis. However, the absence of overt signs of inflammation like warmth, erythema, and the intermittent nature of multiple joint involvement make it less likely. Radiographs have low sensitivity for osteomyelitis in the first 10 days after the onset of infection. Bony changes like periosteal reaction are seen earliest at 1 week.¹⁶  In the absence of other symptoms, travel history, visits to petting zoos or endemic areas, and exposure to farm animals, livestock, or pets like cats and turtles, diseases like brucellosis, bartonellosis, tuberculosis, or enteric fever are unlikely. Parvovirus B19 disease¹⁷  and brucellosis¹⁸  can present with fevers, joint pains, and cytopenias. Our patient never had the classic slapped-cheek rash of parvovirus disease. There is no reason to suspect brucellosis in this patient without a history of consumption of unpasteurized milk, undercooked meat, or history of visit to endemic areas.

Given that no infectious causes were identified (see Table 2), a more extensive rheumatologic workup was initiated. However, results were not immediately available.

Fever is a common manifestation for many childhood rheumatic diseases including childhood systemic lupus erythematosus (cSLE), dermatomyositis, vasculitis, sarcoidosis, and systemic-onset juvenile idiopathic arthritis (so-JIA). In these patients, the diagnosis is often a challenge because there are numerous potential rheumatologic diagnoses, many of which lack specific laboratory tests. The clinician has to rely on pattern recognition and judicious use of testing to establish the diagnosis. Prolonged fever associated with elevated inflammatory markers and joint pain suggest the diagnosis of so-JIA. The disease affects boys and girls equally and is characterized by a fever associated with arthritis, rash, polyadenopathy, liver, and spleen enlargement.¹⁹  It is noteworthy that the interval between the onset of systemic signs and the appearance of arthritis may be as long as 10 years, and approximately one-third of patients will only have arthralgia during the first weeks of the disease. Because there are no specific laboratory tests for so-JIA, the diagnosis is essentially clinical.

Children with vasculitis such as polyarteritis nodosa, granulomatosis with polyangiitis, and Takayasu disease can also present with prolonged high fever, muscle pain, skin rash, and/or arthritis. Modern imaging has revolutionized the ability to diagnose large-vessel vasculitis. MRI and magnetic resonance angiography are used to detect large-artery lesions, thus avoiding more invasive imaging studies such as conventional catheter-based angiography. This approach has become the standard practice to screening for large-vessel vasculitis.²⁰ 

An MRI of the chest revealed trace pleural effusions bilaterally. An MRI of the abdomen and pelvis and magnetic resonance angiography of chest, abdomen, and pelvis were obtained and were normal.

The differential diagnosis for FUO includes malignancies like acute leukemia, lymphoma, neuroblastoma, and sarcomas, as well as histiocytic disorders such as hemophagocytic lymphohistiocytosis (HLH). Prolonged fever, presumed to be secondary to cytokine release, is a common presentation for pediatric leukemia and lymphoma and is found in up to 60% of patients at the time of diagnosis.²¹  With neuroblastoma and sarcoma, fever usually presents in the setting of metastatic disease. Another common presentation of hematologic malignancy is joint pain, which is thought to be secondary to marrow infiltration and expansion. In a patient with FUO, joint pain, and associated cytopenias, it is reasonable to begin evaluation of malignancy with CBC, reticulocyte count, peripheral blood smear, comprehensive metabolic panel, lactate dehydrogenase (LDH), and uric acid. Imaging should include computed tomography or MRI of the neck, chest, abdomen, and pelvis to evaluate for pathologic lymphadenopathy as well as the presence of a mass.

HLH²²  is another hematologic condition that should be considered in the presence of prolonged fever. Macrophage activating syndrome²³  is a form of HLH that primarily occurs in patients with an underlying rheumatologic condition. Our patient did not have a history of autoimmune disease; hence, macrophage activating syndrome was not discussed. Given the combination of prolonged fever, joint pain, and cytopenias, a workup for malignancy was undertaken first. CBC revealed mild normocytic anemia (10.8 g/dL) with mean corpuscular volume of 83.9 fL and a reticulocyte count of 1.2%. The calculated corrected reticulocyte count is 0.9%, which is low, suggesting inappropriate erythropoiesis. The differential for normocytic anemia with low to normal reticulocyte count includes malignancy, myelodysplastic syndrome, transient erythroblastopenia of childhood, bone marrow failure syndrome, infection, drug-induced anemia, lead poisoning, acute blood loss, or chronic inflammation. The remainder of the CBC, including an absolute neutrophil count and absolute lymphocyte count, was normal. LDH and uric acid were within normal limits. Review of peripheral blood smear supported the finding of normocytic anemia. There were only a few ovalocytes and teardrop cells present, with no evidence of basophilic stippling, malignant cells, or hemophagocytes. Although ovalocytes and teardrop cells can be found in conditions such as myelofibrosis, myelodysplastic syndromes, and thalassemia, these can also be nonspecific findings. After a thorough review of the results with normal imaging studies, we had a low suspicion for malignancy in this patient.

Because an oncologic process was moved lower on the differential, a presumptive diagnosis of so-JIA was made, and anakinra (interleukin 1 [IL-1] inhibitor) was started. After 48 hours of starting anakinra, there was no improvement in the patient’s clinical symptoms. Repeat laboratory evaluation now revealed cytopenias in 2 cell lines (white blood cell and Hb; see Table 1), mild transaminitis as well as elevated ferritin >1000 ng/mL.

The most common initial clinical features in so-JIA are fever, arthritis, and rash. There are no diagnostic criteria for JIA; however, we do use the International League of Associations for Rheumatology classification criteria designed for clinical research to diagnose patients with so-JIA.²⁴  It is noteworthy that some patients may not fulfill this definition initially because of the strict definition of fever and lack of arthritis. Our patient met the diagnosis of so-JIA by having arthritis, daily fever for >2 weeks, and the presence of pleural effusion on MRI suggesting serositis. Additionally, the patient was fatigued and ill-appearing at the time the diagnosis was made, which are symptoms classically seen in patients with so-JIA.

The proinflammatory cytokines play a central role in so-JIA pathogenesis. As a result, the 2013 update of the 2011 American College of Rheumatology recommendations outlines²⁵  the indications for use of IL-1 and interleukin 6 inhibitors for the treatment of so-JIA. In a multicenter uncontrolled retrospective study of patients with so-JIA treated with IL-1 inhibitors, a rapid resolution of systemic symptoms, typically within 1 to 2 days, occurred in ∼90% of patients.²⁶  The use of anakinra as a first-line treatment in a presumed patient with so-JIA allows the clinicians to promptly assess the proinflammatory response while waiting on a final diagnosis. It was of concern that our patient did not show improvement while on IL-1 inhibitor.

Because of the lack of improvement after initiation of cytokine inhibition, it is appropriate to revisit the diagnosis of malignancy, as well as a marrow infiltrative process of production abnormality. Malignancies such as T-cell lymphoblastic leukemia, lymphoma, neuroblastoma, germ cell tumors, pleuropulmonary blastoma, skin tumor, and metastatic solid tumors, may present with malignant pleural effusions. With trace bilateral pleural effusions, these malignancies would be highly unlikely, especially with otherwise normal imaging. Normal imaging in the setting of bicytopenia may rule out metastatic malignancy but would not sufficiently eliminate the possibility of a hematologic malignancy, such as leukemia. The presence of bicytopenias and persistent fever is also suspicious for HLH. To evaluate for both, a bone marrow aspiration and biopsy were obtained. Examination of marrow components not only assess for malignancy but also hemophagocytosis, cellularity, fibrosis, myelodysplasia, reactivity, metabolic disorders, iron status, and megaloblastic changes. In our patient, marrow revealed normal cellularity and trilineage hematopoiesis without leukemic blasts, dysplastic changes, and hemophagocytes. Given this, malignancy was taken off the differential. In terms of HLH, patients must meet 5 out of 8 criteria for an official diagnosis. These include fever, cytopenias affecting 2 lineages, splenomegaly, fasting hypertriglyceridemia (>2 times upper limit of normal) and/or hyperfibrinogenemia (<2 times upper limit of normal), hemophagocytosis in bone marrow or spleen or lymph nodes, low or absent activity of natural killer cells, ferritin >500 µg/L, and soluble interleukin 2 receptor alpha >2400 U/mL.²⁷  Our patient did have a fever, bicytopenia, decreased natural killer function, and elevated ferritin of 1101 ng/mL; however, with fasting triglycerides of 200 mg/dL, fibrinogen of 354 mg/dL, soluble interleukin 2 receptor alpha of 492 U/mL, and no hemophagocytosis, HLH was eliminated as a diagnosis.

With no improvement in symptoms, Il-1 inhibitor was stopped after 72 hours. The patient’s antinuclear antibodies (ANAs) and anti–double-stranded DNA (dsDNA) antibody resulted on day 19 of illness and revealed positive results. Full rheumatology laboratories are presented in Table 3. A final diagnosis of cSLE was made.

cSLE has protean clinical manifestations that can affect virtually every organ and can vary from patient to patient. The patient’s initial clinical picture can be indistinguishable from that seen in so-JIA. Although an ANA is the hallmark of lupus, an ANA alone is nonspecific and detectable in many other disorders including autoimmune diseases (so-JIA, dermatomyositis, autoimmune hepatitis, Hashimoto disease, inflammatory bowel disease)²⁸  and hematologic and solid tumor malignancies.^29–31  Mild transaminitis can be seen in so-JIA and systemic lupus erythematosus (SLE) as well as in viral illness. Liver test abnormalities in SLE are relatively common, but clinically significant liver disease is rare.³² 

The lupus classification criteria³³  is useful for structuring the approach to the investigation and enhance the ability to differentiate lupus from other connective tissue disorders. Initially, lupus can be difficult to diagnose because the symptoms are nonspecific and overlap with those of more common conditions like a viral illness. On admission, the patient did not seem to meet the criteria until additional symptoms emerged. As his disease progressed, additional rheumatologic evaluation with blood tests and imaging were necessary. During his hospital admission, he fulfilled the clinical and laboratory criteria for lupus (arthritis, pleuritis, anemia, with positive ANA and anti-dsDNA antibody results). The anti-dsDNA antibodies are relatively specific for SLE but can also be seen in infections and malignancy.³⁴ 

It is possible that the patient’s initial GI symptoms were related to SLE because GI involvement occurs in ∼20% of children with SLE.¹⁹  However, the majority of GI symptoms in patients with lupus are caused by adverse medication reactions and viral or bacterial infections.³⁵  Our patient’s MRI did not reveal features pertinent to lupus-related conditions such as peritonitis, enteritis, pancreatitis, or mesenteric vasculitis. In addition, he did not have elevated BP during his hospital stay and had normal urinalysis results; hence, renal involvement was not considered.

The patient was started on intravenous methylprednisolone at 2 mg/kg per day on day 20 of illness in addition to omeprazole. His fever and joint pain resolved within 24 hours, and he had increased energy and appetite. Azathioprine and hydroxychloroquine were added as steroid-sparing agents. Subsequently, he was discharged from the hospital on oral steroid, azathioprine, and hydroxychloroquine.

He was seen at the rheumatology clinic 2 weeks after discharge. He did not have joint pain or fevers. His appetite and energy were back to baseline. Repeat laboratories obtained 8 weeks later revealed resolved transaminitis with normal Hb, ESR, and ferritin. He is currently doing well on immunosuppressant therapy with no renal or other organ system involvement.

cSLE is a chronic inflammatory disease of unknown etiology with a heterogeneous range of clinical and serological manifestations. Adding to the complexity of cSLE is the unpredictability of flares or periods of increased inflammatory disease activity as well as the accrual of organ damage. The median age of presentation is 12 to 13 years, and it affects girls more often than boys, even in the prepubescent age group. This makes our patient’s demographics unique for cSLE. The estimated prevalence of cSLE is 9.73 per 100 000 children, with an incidence rate of 2.22 cases per 100 000 children a year.³⁶  African American children with cSLE are known to have a younger age of onset, higher rates of end-stage renal disease, and greater likelihood of disease progression and death.

The presentation of cSLE is diverse, and lupus can affect any organ. Common presentation includes fever, joint pain, and malaise. A high index of suspicion is needed because the typical findings of cSLE are often absent at the onset of disease. The diagnosis is made by an experienced physician on the basis of the combination of clinical symptoms and laboratory results. The American College of Rheumatology criterion exists for lupus; however, the intended use of the classification criteria is for clinical research.³⁷  Not all patients meet the criteria, and there is no criterion for possible or probable lupus. If ≥4 of the criteria are met, including at least 1 clinical and 1 immunologic criterion in the absence of another explanation for the findings, a diagnosis of cSLE is made.³³  An alternative requirement is positive ANA or anti-dsDNA antibody results in conjunction with biopsy-proven lupus nephritis.

The standard treatment of cSLE includes corticosteroids and immunosuppressive, antimalarial, and cytotoxic agents. The goals of therapy are to achieve the lowest possible disease activity, prevent end-organ damage, minimize drug toxicity, and ensure long-term survival. Patients with cSLE have a more severe disease requiring more aggressive immunosuppression than adult SLE with renal disease. Medication complications remain the highest cause of mortality in this group of patients.

We thank all physicians from the Divisions of Hospital Medicine, Infectious Disease, and Rheumatology at Akron Children’s Hospital who were involved in taking care of this patient. We also thank Jennifer Clark, medical writer from Rebecca D. Considine Clinical Research Institute, for reviewing our article and providing us with valuable suggestions.

ANA

antinuclear antibody

ASO

antistreptolysin O

BP

blood pressure

CBC

complete blood count

cSLE

childhood systemic lupus erythematosus

dsDNA

double-stranded DNA

ED

emergency department

ESR

erythrocyte sedimentation rate

FUO

fever of unknown origin

GAS

group A Streptococcus

GI

gastrointestinal

Hb

hemoglobin

HLH

hemophagocytic lymphohistiocytosis

IL-1

interleukin 1

KD

Kawasaki disease

SLE

systemic lupus erythematosus

so-JIA

systemic-onset juvenile idiopathic arthritis