Children will often be brought to the primary care provider’s office with complaints that seem relatively straightforward and are treated accordingly. The issues for the provider are twofold: maintaining a degree of healthy hesitation in arriving at the diagnosis, and being willing to reevaluate progress, or lack thereof, for the patient who has been sent down a management pathway. The correct diagnosis can sometimes be elusive and require thought and careful consideration of the possible differentials and the most appropriate tests for a problem. In developing a differential diagnosis based on the presentation of the patient, there are sometimes several opportunities where diagnoses can be missed. It is important to use the most specific and sensitive diagnostic tests while keeping in mind their accuracy, precision, and cost. This case will illustrate some of these points.
1. Apply key points in the history and physical examination to develop a differential diagnosis.
2. Discuss the variety of pathogens responsible for pharyngitis and infectious mononucleosis.
3. Understand how sensitivity and specificity of laboratory tests aid in the development of the differential diagnosis.
4. Understand how ethnic, cultural, and personal factors play a role in shared decision making when developing a diagnostic and treatment plan.
Case Presentation and Discussion
Maya Santiago is a 7-year-old American with a Peruvian father and a Puerto Rican mother. She presents with a 6-day history of a sore throat associated with fever to 103°F (39.5°C), headache, malaise, painful lymphadenopathy, and overwhelming fatigue. On day three of the illness, Maya was seen for pharyngitis. She was diagnosed with streptococcal pharyngitis after a rapid strep test was positive and was started on Omnicef at 14 mg/kg/day due to a history of rash following Amoxil. The child is worse after 3 days of antibiotic. The mother is concerned that there is something else wrong with the child.
What questions will you need to ask the family related to the presenting complaints?
Compliance to medication is an important history point.
The child and mother confirm that they have been taking the antibiotic on a twice a day schedule using a measurer.
In doing a follow-up visit, the healthcare provider can employ the pneumonic NEEDS, which can be a helpful tool to remind the provider about key areas to explore relative to the child’s current disposition. NEEDS stands for Nutrition, Elimination, Education/Environment, Development/Daycare, and Sleep/Sexuality.
Nutritionally, the child reports she is able to drink cool liquids, puddings, ice cream, and warm soups. Regarding elimination, she is voiding at least six times a day and has a small, brown, formed stool daily. Education and environment screening indicates that she is in second grade and doing well. She has not been exposed to any sick friends or family members. Concerning development/daycare, she goes to a daycare center for an after-school program as well as being involved in gymnastics 3 days a week, although she has not attended this week. Finally, for sleep assessment, she reports taking at least two naps a day and sleeping 12 hours a night for the past 4 days. Normally she does not take naps and sleeps about 9 hours a night.
Maya’s mother reports giving Advil at an appropriate dosage (10 mg/kg/dose) every 6 hours for the persistent fever. She denies the use of any other alternative medication. The child feels worse than she did 3 days ago despite the Advil and the Omnicef. The mother reports that Maya is usually very energetic, and her present behavior is unusual. The mother also denies any history of high persistent fever(s) or serious illnesses in the past.
Due to the lack of response to antibiotic and the presence of lymphadenopathy, fatigue, persistent fever, and tonsillitis, you consider infections such as infectious mononucleosis (IM), which would include signs and symptoms such as Maya’s that do not improve with antibiotic treatment.
What other questions do you need to ask Maya and her mother?
Before answering this question, here is some background information about pharyngitis and infectious mononucleosis (IM) that may be helpful to you. Pharyngitis is the third most common complaint in pediatric primary care settings. In this case, the complaint is more complex than a simple pharyngitis and points in the direction of IM with a secondary group A streptococcus infection. You need to consider the pathophysiology, epidemiology, differential diagnosis, and cultural factors before answering this question.
Pathophysiology of Infectious Mononucleosis
A sore throat presents with pain localized to the pharynx, surrounding anatomy, and the neck and is accompanied by dysphasia. The younger the child, the greater the difficulty in identifying the area of painful symptoms. A history of fever and decreased oral intake is one of the signs of pharyngitis in a nontoxic child. There may be accompanying fever, pharyngeal exudates, tonsillar enlargement, uvula inflammation, headache, palatal petechiae, ulcers of the tonsillar pillars, and soft palate, along with anterior cervical lymph node enlargement (Bisno, Gerber, Gwalty, Kaplan, & Schwartz, 2002). The etiology with acute infectious pharyngitis includes bacteria and viruses (see Table 16-1).
IM varies from a simple pharyngitis in that the course is prolonged with fever, lymphadenopathy, and fatigue. Epstein-Barr virus (EBV) is responsible for up to 90% of infectious mononucleosis in adolescent and adults (Hurt & Tammaro, 2007); however, in younger children, the infection is generally sub-clinical (Hurt & Tammaro; Rezk & Weiss, 2007). The term IM indicates a constellation of symptoms that arises from infection with a host of viruses including EBV; however, 10% of IM-like pediatric cases are caused by cytomegalovirus (CMV), human immunodeficiency virus (HIV), or toxoplasmosis infection (Hurt & Tammaro; Smellie et al., 2007). Thus, although the majority of cases of IM are from EBV, other causes need to be considered.
EBV infects the B lymphocytes of the lymphoid-rich areas of the oropharynx, which disseminate the infection in the lymphoreticular system (Rezk & Weiss, 2007). This predilection of EBV to entrench itself within the lymphoreticular system allows for a reservoir of EBV within the B-cells and causes its persistence. The persistence of EBV genes in B-cells results in viral latency and a carrier state (Rezk & Weiss). In addition, EBV-specific cytotoxic T-cell lymphocytes control acute infection and reactivation of infection (Kimura, 2006). This T-cell activation causes production of interleukin 2 and cytokines, causing atypical lymphocytes to appear on a complete blood count (Kimura). The clinical illness of IM may reflect cell damage in the oropharynx caused by viral replication, B-cell proliferation with a rise in cytokine levels, and immunopathology due to the immune response to the virus (Vetsika & Callan, 2004).
CMV has the largest genome size of any virus that infects humans and is a member of the human herpes virus. Human herpes viruses all establish viral latency in the cells they infect; thus, they can reoccur or shed intermittently (Adler & Marshall, 2007). The inner core of viral DNA is contained in a capsid surrounded by a tegument layer and an outer layer composed of glycoproteins. The antigenic glycoproteins trigger an immune response, which includes T-cells (Adler & Marshall). CMV viral DNA can be found in megakaryocytes, monocytes, dendritic cells, and myeloid progenitor cells (Soderberg-Naucler et al., 2001). Reactivation is more likely to occur when the human host is immunosuppressed. Incubation is estimated to be between 1 and 2 months (Adler & Marshall).
Acute infection with HIV was first described as a monolike illness in 1985 (Cooper et al., 1985). After a period of incubation of 2–4 weeks following an acute infection, patients can develop sore throat, malaise, myalgias, arthralgias, nausea, and headache. A nonpruritic maculopapular rash can also be seen (Hurt & Tammaro, 2007).
Toxoplasmosis is the main protozoal cause of a mononucleosis-like illness that can present with rather mild constitutional symptoms of pharyngitis, maculopapular rashes, nontender cervical or occipital lymphadenopathy, and hepatosplenomegaly. This is a self-limited illness and resolves spontaneously over a few months.
Table 16–1 Common Infectious Agents and Acute Pharyngitis
EBV is transmitted via saliva between individuals and has an incubation period of 4–7 weeks (Vetsika & Callan, 2004). After incubation, pharyngitis, lymphadenopathy, splenomegaly, and fatigue occur. The elevation of transaminases (SGPT, SGOT), indicating a hepatitis, may be evident but jaundice is present in less than 10% of patients (Vetsika & Callan).
CMV is excreted in nearly all body secretions except tears (Adler & Marshall, 2007). Transfusion of CMV-infected blood into a CMV-negative person can cause CMV infection and has been rarely reported as a result of nosocomial contact within a hospital. CMV-caused IM (CMV IM) in children, adolescents, and adults can occur in situations involving close contact with children under age 2 years. Daycare workers and school teachers are at higher risk (Hurt & Tammaro, 2007). Whereas sore throat, fatigue, and malaise are prominent features of IM, CMV IM presents with less prominent lymphadenopathy, pharyngeal erythema, and splenomegaly. Elevated transaminases occur much more commonly with CMV IM.
Toxoplasmosis is found throughout the world, and the members of the cat family are the host. Cats get the infection from eating mice or uncooked meat. The cat sheds the oocyst 3 to 30 days after the ingestion. Transmission also can occur through transfusion or transplantation. Mothers can also transmit the infection to their unborn children. The clinical presentation after the newborn period includes fever, sore throat, lymphadenopathy, and malaise (Pickering, Baker, Long, & McMillan, 2006).
Cultural and Ethnic Aspects
The Hispanic American population is the second largest and fastest-growing population in the United States. To deliver culturally effective pediatric care, the provider needs to understand the beliefs, values, and customs of the population (American Academy of Pediatrics, Committee on Pediatric Workforce, 2004). Flores (2000) identified five normative cultural values that are highly valued by Hispanics and are important to consider in interpersonal interactions:
• Simpatia, or kindness expressed to family in times of stress
• Personalismo, or formal friendliness
• Respeto, or admiration
• Familismo, or loyalty to family
• Fatalsimo, or the belief that fate cannot be altered
In addition, some Hispanic cultures believe in the “hot–cold” theory and others believe in subtle variations of this theory (Hardwood, 1971). The hot–cold theory of illness is centered on the belief that the body reacts to heat and cold. Some illnesses, often including symptoms of redness or swelling, are classified as hot. Other illnesses such as respiratory infections are cold. Cold illnesses require hot remedies, and hot illnesses are treated with cold foods.
In caring for this family, the provider needs to determine how the parent’s ethnic beliefs would affect the care of the child. It is important to show respect for the mother’s culture and country as well as formal friendliness by introduction as a primary care provider. It is essential to give an appropriate amount of simpatico about her daughter’s illness. The mother thinks of herself as more American than Puerto Rican and denies belief in the hot–cold theory of disease.
The oncological differential diagnosis for infectious mononucleosis includes acute leukemia, Hodgkin’s disease, non-Hodgkin’s lymphoma, and solid tumors of the neck. The differential diagnosis for pharyngitis includes bacterial, viral, and protozoal causes (see Table 16-1). Many infectious agents have seasonal prevalence, and some infectious agents are more common in different age groups. Allergies can also cause throat pain or pharyngeal tickling, but would not be accompanied by a fever. Acute sinusitis could present with fever, headache, pharyngitis, and cervical adenopathy, but frequently presents with congestion and purulent nasal discharge.
From the above review, what other information do you need to obtain?
• Are other family members ill or have they been ill in the past 2–3 months?
• Have close friends been ill in the past 2–3 months? (exposure to infectious diseases)
• Is the child in the after-school program involved with the children in the daycare? (exposure to CMV)
• Is the child taking any medication for health? (explores alternative medication use)
• Has the child been in school over the past week? (confirms fatigue and nature of illness)
• Has the child been in contact with pets, especially cats? (looks for toxoplasmosis)
• Has there been any recent travel? (exposure to different infectious agents not seen in the United States)
• Is there any history of sexual assault? (possible HIV exposure)
• Does the child have a history of allergic rhinitis? (allergies)
• Has the family seen any other providers regarding this illness? (integrative medicine approach)
No one has been ill in the household or among the child’s close friends. The child is not taking any medications for health and has not been to any other provider. The child is exposed to the daycare children in the after-school program or in her gymnastics class, where the children all use the same equipment. There is no known exposure to cats or other pets. The child has no allergies and has not been sexually assaulted.
What information do you want to collect in your physical examination?
Physical Examination: Height, weight, blood pressure, and body mass index are all on the 50th percentile for this Tanner 1 female who has not had any weight loss. The physical examination is remarkable for +3 erythematous tonsils without exudate. There are palatal petechiae on the soft palate. The anterior cervical chain is mildly tender and nodes range in size from 2–2.5 cm. The tonsillar nodes are 2 cm. The nodes are not fixed or mattered. On the right side, there is a 3 cm node on the posterior chain with a few nodes that are less than 1 cm around it. These nodes are not fixed but are tender to touch. There is no axillary, epitrochlear, inguinal, or popliteal nodes. The chest is clear and the heart sounds are normal without murmurs. There is no hepatosplenomegaly or abdominal masses present. The external genitalia is without redness, and the hymenal ring is smooth and without increased redness on gross inspection. The skin is clear without rash or petechiae.
Making the Diagnosis
The history and physical examination are consistent with IM. The family is anxious for laboratory confirmation of the diagnosis.
What initial laboratory diagnostic tests need to be ordered?
Laboratory tests are ordered to confirm a suspected diagnosis. Before ordering laboratory tests, consider the following points:
• What is the expense of the test?
• If the patient had no insurance, would you order the test?
• Which test has the lowest cost and will best help you determine the diagnosis?
• Do you know how to interpret the test including sensitivity, specificity, and predictive value for the child’s age?
• How will the lab test help you in developing a plan of care for the patient?
• Will the test satisfy the family’s concerns and need for further testing?
If the wrong test is ordered, the diagnosis will be delayed. In order to choose a diagnostic test, it is important to consider the test’s specificity and sensitivity and to recognize that these can vary with the age of the child. These concepts are explained further in Table 16-2. In trying to determine which test to order, sensitivity, specificity, prevalence, predictive value, and cost must be considered. The main reason to investigate with serology is to confirm the cause of symptoms.
An initial diagnostic strategy would be to do a heterophile antibody test (Bell & Fortune, 2006; Smellie et al., 2007) and a complete blood count (CBC) to look for lymphocytosis and atypical lymphocytes. Each is discussed here.
The Paul Bunnell heterophile antibody is a group of IgM class immunoglobulins that are present when someone has an acute EBV infection. The structurally similar epitropes in the nonhuman RBC (sheep, horse, pig) in the test react with the Paul Bunnell heterophile antibody, resulting in red cell agglutination. In adolescents and adults, up to 85% who have clinical IM have detectable Paul Bunnell heterophile antibodies. The antibodies develop during the first week and peak between the second and fifth week of illness (Hurt & Tammaro, 2007). The range of sensitivity for this test is between 71% and 90% (Linderholm, Boman, Juto, & Linde, 1994); however, the results of heterophile antibody testing is lower in children under 12, ranging from 25–50% (Bruu et al., 2000). During the first week of illness, there is a 25% false negative rate (Ebell, 2004).
Table 16–2 Understanding Sensitivity and Specificity
Rapid Monospot tests are enzyme-linked immunosorbent assay (ELISA) techniques to look for EBV virus infection. Rapid tests may be available in the office depending on insurance reimbursement. Thus, a positive heterophile antibody test or Monospot test indicates that the child has EBV IM; however, a negative Monospot in this girl may mean that the test was done too early in the course of the illness, the child will not react because she is young, or the child has a heterophile-negative mononucleosis-like illness caused by CMV, HIV, or toxoplasmosis. Thus for younger children, this test may not be as helpful.
The CBC during the first week of illness may not show lymphocytosis or increased atypical lymphocytes. As the number of atypical lymphocytes increase, the specificity of the test increases. Remembering the mnemonic SPINhelps: A high SPecificity rules IN disease. When the number of atypical lymphocytes is greater than 10%, the sensitivity is 75% and the specificity is 92%. When it goes up to greater than 40%, the sensitivity is 25% and the specificity is 100% (Bell & Fortune, 2006). (See Table 16-2.) Thus, the higher the atypical lymphocyte count, the greater the likelihood of IM.
You make a presumptive diagnosis of IM based on Maya’s history and clinical findings and begin your discussion with her mother regarding the management plan and laboratory testing that you will do to confirm your IM diagnosis. The reason that a presumptive diagnosis is made at this time is based on the fact that Maya’s course of illness is six days in duration and the Monospot test can come back negative during the early course of illness, thus, giving a false negative result.
How do you plan to treat the child’s infectious mononucleosis?
Therapeutic plan: What will you do therapeutically?
The plan is symptom-based and customized to the child’s presentation and the family’s desires. The goals are to:
• Control fever
• Keep the child hydrated
• Provide enough calories to prevent weight loss
• Allow adequate rest opportunities
• Treat secondary bacterial infections
• Provide opportunities to do school work by coordinating with the school for homework and, if the illness continues, a home tutor
• Avoid splenic rupture by limiting contact play or sports
• Determine the cause of the IM
Treatment for EBV and CMV IM is symptom based. The use of antipyretics to control fever and keeping the child in light clothing to allow for heat dissipation is important. Appropriate foods and liquids that avoid irritating the throat need to be suggested with cultural sensitivity. Discussing what foods Maya eats and choosing which ones might be tolerated is helpful to the family. Liquids that would be tolerated are selected with input from the family. Because group A streptococcus is a secondary infection for patients with IM, the family is encouraged to finish the Omnicef. At this point, the mother is given a note for the school for school work and the need for a home tutor. Each school system determines the length of time that a child must be out before a home tutor is allowed during a prolonged illness; however, giving the school notice that an illness is likely to be prolonged can help them plan and get the tutor in the house sooner.
There is no medication to treat EBV or CMV IM. The use of acyclovir has not proved to shorten the course of illness (Torre & Tambini, 1999). A recent Cochrane review noted there was insufficient evidence to recommend steroid treatment for symptom control in IM (Candy & Hotopf, 2008). There was also a lack of research on the long-term side effects in patients treated with steroids, including lymphoproliferative disorders (Candy & Hotopf).
Educational plan: What will you do to educate Maya and her family about IM?
A discussion with the family about the evaluation for causes and the symptomatic treatment of the IM is important. Points that are raised in the discussion include:
Explanation of the diagnosis, the variability of the course of IM, and the lack of specific treatment for IM.
Education regarding dosage of antipyretic and fever management. Discuss fever and keeping the child cool by not using multiple blankets. Also educate regarding the dangers of alcohol baths to reduce fever.
Explanation of the importance of treating the secondary bacterial infection, despite the fact that it might not make the fever, fatigue, or sore throat disappear.
Discussion about the possibility of splenic enlargement and that contact play therefore should be avoided, including gymnastics classes.
Discussion of the importance of hydration, even if the child will not eat food with close monitoring of oral intake and urine output.
Instructions to monitor for any respiratory problems from enlargement of tonsils and allow for naps as well as a longer sleep period at night.
You assure the family that you will closely follow up in the office after the laboratory testing is done and will be available by phone for any questions.
Discuss further laboratory testing to determine the specific infectious agent responsible for the child’s IM.
The family wants to know the exact cause of Maya’s illness because there are four other children in the household and more than 20 cousins whom the family sees on a regular basis. After discussion of the treatment plan, Maya’s mother is instructed to get the lab work done in 2 days to increase the specificity of the testing. The results from day 8 of the illness show a negative Monospot test with a CBC with 78% lymphocytes and 18 atypical lymphocytes. The child returns on day 10 of illness with a predominance of fatigue and fever. The child still complains of a sore throat and painful lymph nodes. The physical examination is unchanged and no hepatosplenomegaly is found. You decide to do additional laboratory testing. Liver function tests and EBV-specific antibodies are ordered to confirm the suspected diagnosis of EBV mononucleosis.
EBV-specific antibodies include IgM and IgG against the viral capsid antigen (VCA), Early antigen (EA) diffuse staining, and EBV nuclear antigen (EBNA). The two tests that are most helpful in diagnosing active and recent infections are the IgM anti-VCA and the EA. IgM levels go up in acute infection and decrease over 3 months. Early antigens are present at the onset of clinical illness and decrease as the infection resolves, usually over 6 weeks. Early antigens are not present once the symptomatic period is ended. Another antibody that can be assayed is IgG antibodies to viral capsid antigen, which will rise 6 to 12 weeks following the EBV infection and remain elevated for life (Ebell, 2004). EBNA are long-term antibodies that do not rise until several weeks to months after the onset of infection. These are not found in acute infection and are a marker of EBV infection in the past (Pickering et al., 2006).
CMV can also cause elevation of the IgM antibodies to VCA. The sensitivities of the tests range from 95% to 100% and the specificities of the test range from 90% to 100%, depending on the laboratory test manufacturer (Bruu et al., 2000).
The results of laboratory testing done on day 10 of Maya’s illness are back. The child’s tests for IgM VCA, EA, IgG VCA, and EBNA are all negative. The aminotransferases (AST and ALT) are both elevated five times above normal, reflecting a mild hepatitis. The bilirubin and alkaline phosphatase levels are within normal limits, indicating no biliary obstruction. The family is called with the results of the serology and is asked to return in 2 days for reevaluation. At this time, the fever is starting to come down but the fatigue persists. The diagnosis of EBV-negative mononucleosis is considered, and given the attendance at a daycare center after-school program and the predominance of fatigue and fever in the presentation, CMV serology for anti-CMV IgM and IgG is ordered (see Table 16-3). The family persists in wanting to know the exact cause of the illness and wants the additional serology tests done. The plan is to continue to symptomatically treat the child’s fever with Advil, allow for rest, provide fluids and foods the child can tolerate, keep the child home from school, limit rough play, and maintain infection control measures to prevent household spread.
Table 16–3 Laboratory Testing in Infectious Mononucleosis (IM)
Sources of Diagnostic Error
In developing an initial differential diagnosis, the clinician’s past experience plays a significant role in what diagnostic possibilities are considered (Redelmeier, 2005). Other pitfalls include a reliance on initial impression and not reconsidering other diagnoses in light of new data obtained during reevaluations as well as making a decision about a diagnosis based on how the information is presented (framing). Framing effects cause small changes in wording to alter management decisions (Redelmeier). Additionally, clinicians can rely heavily on diagnostic technology or an assertive colleague’s opinion. To overcome these possibilities, a person must reconsider their diagnostic options when the colleague is more distant. Lastly, the clinician may prematurely close the diagnostic possibilities; this is known as premature closure (Redelmeier). In this case, the predominance of fever, fatigue, lack of exudative tonsillitis, and significant elevations of transaminases all pointed to CMV (Hurt & Tammaro, 2007). Because most cases of IM are EBV related, the diagnosis needed to be reconsidered in light of the negative serology and the persistent illness.
The serology to diagnose CMV includes anti-CMV IgM, spin-amplified urine culture for CMV with pp65 antigen detection, and CMV PCR. In this case, the least expensive test was ordered because the child was slowly improving. The anti-CMV IgM was significantly elevated.
The results come back on day 21 of illness; the child’s fever is effervescing, and the child is starting to take shorter naps. The school is sending in a tutor and the child is able to stay up for longer periods. A reevaluation is done after 7 days. One month after the initial presentation, the child is improved enough to go back to school, but gymnastics classes are not allowed during the first week of resumed school attendance to make sure the child is able to handle school academics before gymnastics is added.
When should the child with IM be allowed to participate in sports?
Splenic rupture is most common within 4 to 21 days after the onset of symptoms (Waninger & Harcke, 2005). Usually during the first few weeks of infection, there is spleen enlargement as a result of lymphocytic infiltration. Although splenomegaly is more common with EBV IM, it can occur with heterophile-negative mononucleosis (Hurt & Tammaro, 2007). Although some authors recommend imaging the spleen prior to return to play, there is variability in the normal size of the spleen in children (Waninger & Harcke). Clearly before an athlete returns to play, he or she should be afebrile, well hydrated, and free from the symptoms of IM. Splenic rupture after 28 days of the onset of illness is rare, but still can occur (Waninger & Harcke). It is important to limit activity in the first 21 days and then, in an asymptomatic athlete, allow a gradual return to play while avoiding activities that put the spleen at risk. The return to full activity should be paced depending on the individual presentation; abrupt increases in exercise should be avoided.
Maya adds one class of gymnastics per week over the next 3 weeks and recovers uneventfully from her CMV IM. The child is followed up 1 month after school was resumed. The family appreciates the concern for the child’s condition.
Key Points from the Case
1. When developing a differential diagnosis, it is important to reevaluate your initial impression based on the developing clinical presentation.
2. Diagnostic testing must be done in an organized fashion considering the most likely diagnosis based on history and physical examination.
3. Sensitivity, specificity, and predictive value are important to consider in the interpretation of laboratory testing.
4. Ethnic, cultural, and personal beliefs must be considered in developing a plan of care for the pediatric patient.
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