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A 4-month-old boy with past medical history of eczema presented with fever and cough; a chest radiograph showed lung consolidation, and he was initially treated with amoxicillin for presumed community-acquired pneumonia. After several days, his fever persisted. He was also profoundly anemic. Antibiotic coverage was broadened because of the concern for resistant organisms; he began to improve and was discharged from the hospital. However, at 5 months of age, his fever returned, and he continued to demonstrate lung consolidation on chest radiograph. Additionally, he had lost weight and continued to be anemic. Splenic cysts were noted on abdominal ultrasound. He was diagnosed with an unusual etiology for his pneumonia and improved with the appropriate therapy. An underlying immunodeficiency was suspected, but initial testing was nondiagnostic. At 12 months of age, he presented with another infection, and the final diagnosis was made.
The patient was a 4-month-old African American boy born at 37 weeks’ gestation with a birth weight of 2.45 kg (10th percentile) and a past medical history of moderate eczema diagnosed at 2 months of age. He initially presented to his pediatrician’s office with fever and cough for 7 days. Chest radiograph showed a consolidation involving the lateral portion of the right middle lobe that was concerning for pneumonia. He was prescribed amoxicillin; however, after 7 days of therapy, he continued to be febrile with a maximum temperature of 102°F. He was referred to the emergency department for further workup. In the emergency department, his vitals included a temperature of 103°F, pulse 173 beats per minute, respiratory rate 22 breaths per minute, and oxygen saturation of 96% on room air. His weight was 5.78 kg (15th percentile) and height was 59 cm (18th percentile). On physical examination, he appeared alert and comfortable. Head, neck, and oropharyngeal examination were normal except for conjunctival pallor. Lung examination demonstrated diminished breath sounds over the right middle lobe. Cardiovascular examination revealed a II/VI nonradiating systolic ejection murmur, strong peripheral pulses, and brisk capillary refill. His abdomen was soft and nontender, without masses or hepatosplenomegaly. His skin was pale with eczematous patches on his face and trunk.
Dr Van Opstal (General Pediatrics), What would be your differential diagnosis and next steps in management for this child?
The child may have a resistant or atypical organism causing his pneumonia. First, I would ensure he had truly received the amoxicillin. I would also be concerned for a complication of pneumonia, such as parapneumonic effusion or empyema. I would also consider pulmonary congenital malformations, such as congenital cystic adenomatoid malformation, pulmonic sequestration, or bronchogenic cysts. Additionally, the child has a murmur. I would want to better characterize the murmur, which could be related to his fever or a clinical sign of anemia, but infectious endocarditis should be considered. Finally, the child could have an additional source of infection, such as a urinary tract infection. Regarding management, he should have blood cultures drawn, a urinalysis and urine culture, and respiratory viral studies. Testing of an acute-phase reactant may also be helpful. Although the Infectious Diseases Society of America guidelines on community-acquired pneumonia1 do not routinely recommend complete blood count with differential, in his case, I would check one, given the physical signs of anemia and the persistent signs of infection. A repeat chest radiograph would also be appropriate. The guidelines for community-acquired pneumonia also recommend admitting children aged 3 to 6 months with concern for bacterial infection. At this time, he appears stable for the general pediatrics floor.
Complete blood count was significant for a white blood cell count of 15.7 th/μL (normal, 5–15 th/μL), hemoglobin of 6.2 g/dL (normal, 9.5–13.5 g/dL), and platelets of 308 th/μL (normal, 150–399 th/μL). Of note, his hemoglobin had been 8.5 g/dL just 1 week earlier. Additionally, his mean corpuscular volume was 73 fL (normal, 76–111 fL) and red cell distribution width was 16% (normal, 11.5%–14.5%). C-reactive protein was 163.5 mg/L (normal, 0–8 mg/L), and his chest radiograph (Fig 1) continued to show a right middle lobe opacity. He was admitted to the general pediatrics floor, and the infectious diseases service was consulted. Ceftriaxone and clindamycin were begun to treat a presumed amoxicillin-resistant pneumonia.
Dr Logan (Infectious Diseases), what would your differential diagnosis be for this infant’s pneumonia, given his failure to respond to typical antibiotic coverage? How should the clinician best evaluate for unusual etiologies of pneumonia?
In a previously healthy 4-month-old infant presenting with fever and a lobar consolidation, the first considerations are common organisms that include viral and bacterial pathogens. The lobar nature of the consolidation increases the likelihood of bacterial infection, and treatment should be directed against typical organisms such as Streptococcus pneumoniae, which would be the most common cause, but Staphylococcus aureus (including methicillin-resistant S aureus) and Streptococcus pyogenes should also be high on the differential. In the case of this infant, it is also significant to note disease progression despite correct initial therapy for community-acquired pneumonia (amoxicillin). In persistent pneumonia (especially in this age group where maternal antibodies are beginning to wane), the clinician must consider untreated common causes of acute pneumonia, progressive disease including necrotizing pneumonia, lung abscesses, empyema, obstructive lesions, bronchiectasis, and congenital abnormalities, as well as myriad uncommon atypical pathogens in which routine antimicrobial therapy would not be effective such as Mycobacterium tuberculosis, Pneumocystis jirovecii, and several other bacteria, viruses, fungi, protozoa, and parasites. A definitive diagnosis should be sought through serologic testing, additional radiologic evaluation (such as ultrasound or computed tomography [CT] scan), and bronchoscopy for microscopy and culture.
Four days later, the patient continued to have intermittent fevers. A CT scan of the chest revealed large areas of consolidation in the lateral segment of the right middle lobe with a few smaller nodular opacities in the bilateral lower lobes (Fig 2). No findings suggestive of cavitary necrosis or empyema were seen. There was no suspicion for congenital conditions, such as bronchopulmonary sequestration or congenital cystic adenomatoid formation. Clindamycin was changed to vancomycin, and azithromycin was added for atypical coverage. Over the course of the next 3 days, the patient’s fever curve gradually began to improve, and blood cultures continued to show no growth. Infectious workup was negative for common respiratory viruses. Serum serology studies testing for Chlamydia, Mycoplasma, and urinary antigen testing for Legionella were also negative. Bronchoscopy was deferred at this time because he was clinically improving. The patient completed 5 days of azithromycin and was discharged from the hospital on 14 additional days of cefdinir and clindamycin. During his hospitalization, the patient’s hemoglobin reached a trough of 5.3 g/dL with a mean corpuscular volume of 71 and red cell distribution width of 16%. Anemia workup was negative for hemoglobinopathies and glucose-6-phosphate dehydrogenase deficiency; parvovirus B19 serologies were also negative. Hematology was consulted and thought his anemia was most likely secondary to acute inflammation. At the time of discharge, he was well appearing, gaining appropriate weight, and had been afebrile for >48 hours. He was discharged from the hospital with close follow-up.
At 5 months old, the patient was noted to have lost 1 kg since hospital discharge (Fig 3), and parents reported the return of fevers. He had been followed closely as an outpatient by a nutritionist, his pediatrician, and infectious diseases. He was breastfeeding with formula supplementation and appeared to have appropriate caloric intake. On examination, he had persistent decreased breath sounds over the right middle lobe. His breathing remained nonlabored, and his oxygen saturation was normal. Hepatosplenomegaly was a new finding. He continued to have eczema and signs of anemia such as conjunctival pallor and pale skin. He was again admitted to the general pediatrics floor where infectious diseases, pulmonology, and immunology were consulted. Laboratory results demonstrated a white blood cell count of 25 th/μL, hemoglobin of 6.6 g/dL, and C-reactive protein of 179 mg/L. His chest radiograph revealed an unchanged right middle lobe consolidation. The patient underwent bronchoscopy, which yielded a positive smear for P jirovecii. He was started on intravenous (IV) trimethoprim-sulfamethoxazole (TMP/SMX) with rapid clinical improvement. An abdominal ultrasound revealed hepatosplenomegaly with multiple hypoechoic nodular lesions in the liver and spleen thought to be consistent with disseminated P jirovecii.
Dr Codispoti (Immunology), when should a general pediatrician be suspicious of an immunodeficiency in a child, and what are the first steps in evaluation for possible immunodeficiency in this particular case?
When infections are unusual, severe, or recurrent, our suspicion rises. We need to see if there are other reasons for the severity or recurrent nature of the infections, secondary immunodeficiencies due to malnutrition, HIV, metabolic disorders (diabetes), environmental insults (radiation), inadequate antimicrobial therapy, and trauma are usually more common. A good starting point is what is recommended by the Jeffrey Modell Foundation in the Ten Warning Signs for Primary Immunodeficiency, which include failure of an infant to gain weight normally, ≥2 pneumonias in 1 year, and the need for IV antibiotics to clear an infection.2 These signs, however, are by no means absolute. Although our patient did not have ≥2 pneumonias, he certainly had an unusual organism, which makes one more suspicious for an immunodeficiency.
The first step in evaluation of immunodeficiency is the complete blood count with differential. This will tell us which individual, or if multiple, cell lines (leukocytes, erythrocytes, or platelets) are affected. If the history is suggestive for deep-seated abscesses, granulomas, atypical mycobacterial infections, or severe infections, especially with opportunistic fungi and viruses, we would check markers of lymphocyte subsets (CD4, CD8, CD19, CD56). We would also check the proliferative capacity of these leukocytes after exposure to antigens (tetanus, Candida) or mitogens (pokeweed, phytohemagglutinin, concanavalin A). If the history is suggestive of sinopulmonary disease or chronic diarrhea, we would check quantitative immunoglobulins (immunoglobulin (Ig)M, IgG, IgA). If these Ig levels are adequate, we would check their functionality by checking antibody response to vaccines, usually both protein (tetanus, diphtheria, Haemophilus influenzae) and polysaccharide (23-valent pneumococcal).
Because of the patient’s history and the etiology of his pneumonia, workup for an underlying immunodeficiency, specifically one affecting the T-cell lineage, was pursued. Immunodeficiency profile (Table 1) revealed normal immunoglobulin, B-cell, and natural killer–cell levels. Absolute CD3, CD4, and CD8 counts were mildly depressed but not to the degree typical in a severe T-cell deficiency. A mitogen stimulation test showed normal T-cell activity, again arguing against a severe T-cell deficiency. HIV 1 and 2 antigen/antibody assays were negative. Fluorescence in situ hybridization probe for DiGeorge syndrome (22q11.2 deletion) was also negative.
After 7 days of IV TMP/SMX, the patient was doing well clinically and ready for discharge. As an outpatient, he completed 3 additional weeks of oral therapeutic doses of TMP/SMX before transitioning to a prophylactic dose. He rapidly gained weight and was following a growth curve just below the 50th percentile; his hemoglobin rebounded to 10.1 g/dL. The patient underwent repeat abdominal ultrasounds to evaluate the hypoechoic structures in the spleen. They had significantly decreased by 6 months of age and were completely resolved at 11 months. Over the course of the next 7 months, he continued to be followed closely by his pediatrician, infectious diseases, and immunology. He underwent genetic testing for syndromes that would most likely explain his constellation of symptoms, including tests for a particular form of severe combined immunodeficiency called IL7R deficiency, which demonstrates a B + natural killer + T phenotype, as was suggested by his immunodeficiency profile, Hyper-IgM (CD40 ligand and CD40), hyper-IgE (STAT3/DOCK8), and Wiskott-Aldrich syndrome; all of these results were normal.
The patient continued to do well until age 12 months, when he presented to his pediatrician with a red and tender cervical lymph node measuring ~4 × 4 cm. There was no appreciable area of Fluctuance, and empirical clindamycin was begun for presumed lymphadenitis. Upon repeat examination 10 days later, there was fluctuance and purulent drainage, but the lesion had decreased to 2.5 × 2.5 cm in size. A culture of the drainage grew TMP/SMX-resistant Klebsiella pneumoniae. His antibiotic was switched to amoxicillin-clavulanate, and he was sent to follow-up with infectious diseases.
Dr Logan, how does the child's presentation with lymphadenitis change the differential diagnosis for his particular underlying etiology?
In itself, having an acute lymphadenitis after being healthy and thriving for 7 months does not suggest any particular diagnosis, especially in a child with significant eczema. A more concerning issue when he presented with lymphadenitis was the organism recovered from the purulent drainage, K pneumoniae, an enteric Gram-negative bacteria from the Enterobacteriaceae family, which is an unusual pathogen to cause lymphadenitis and is most often seen in gastrointestinal and genitourinary tract infections. Typical bacterial pathogens in acute lymphadenitis are S aureus and S pyogenes, common skin flora.4 This unusual Gram-negative bacteria (K pneumoniae) causing lymphadenitis in a male infant, along with a history of atypical pneumonia was highly suspicious for an undiagnosed primary immunodeficiency, in particular, chronic granulomatous disease (CDG), which was now at the top of the differential because of this new Gram-negative lymphadenitis infection in conjunction with his previous history. This disease may have been overlooked previously because other diagnoses more classically associated with P jirovecii were pursued first.
A neutrophil oxidation test revealed an absent neutrophil oxidative burst by dihydrorhodamine 123 fluorescence testing. A diagnosis of X-linked recessive chronic CGD was later confirmed by genetic testing. The patient is currently being treated with prophylactic doses of TMP/SMX, itraconazole, and interferon-γ to prevent bacterial and fungal infections. To date, he has required drainage of 1 additional infected lymph node but has otherwise been asymptomatic. His mother recently revealed that she is pregnant with a girl.
Dr Jones (Genetics), What is the genetic evaluation of a child with CGD? How would you recommend the mother be counseled, given her recent pregnancy?
There are 5 genes associated with CGD: CYBB, CYA, NCF1, NCF2, and NCF3. Mutation in the CYBB gene is the most common cause of CGD. The CYBB gene is located on the X chromosome. It is inherited in an X-linked recessive fashion, seen primarily in males. The CYA, NCF1, NCF2, and NCF3 genes are inherited in an autosomal recessive fashion. A variety of changes have been identified in the CYBB gene, resulting in the CGD phenotype. Nonsense mutation or a deletion of the gene can result in a more severe disease phenotype. Missense mutations between base pairs 1 and 309 usually have milder disease with improved survival. Mutations distal of base pair 309 are more severe. The patient was identified to have a mutation of the CYBB gene at site 469. The risk for the family to have another affected child is dependent on whether this represented a de novo mutation in the oocyte or it was inherited from the mother. If it was inherited from the mother, there would be a 50% chance of passing the disease on to a future male child. In this case, the mother was not a carrier for the CYBB mutation, making it unlikely that she is a carrier (however, there are reported cases of mosaicism). In this case, the recurrence risk in a future pregnancy would be <1%, but to be safe, I would still recommend genetic testing for the known mutation in any future male. There is no need to test a female because she has 2 X chromosomes and would not be symptomatic.
In summary, our patient presented with fever and cough at 4 months of age with a presumed community-acquired pneumonia that was unresponsive to amoxicillin. He also had significant anemia, which was thought to be secondary to inflammation. The patient initially seemed to improve on an antibiotic regimen including coverage for atypical, methicillin-resistant S aureus and penicillin-resistant S pneumoniae. A CT scan of the lungs made congenital pulmonary malformations unlikely. However, despite therapy, after 1 month, he demonstrated poor growth, persistent anemia, and a continued right middle lobe consolidation. Upon bronchoscopy, he was found to have P jirovecii pneumonia (PJP). He also had evidence of hypoechoic splenic structures, initially presumed to be disseminated P jirovecii.
P jirovecii, formerly known as Pneumocystis carinii, is an atypical fungus that can cause pneumonia in susceptible populations.5,6 Serologic studies show that healthy children are infected with P jirovecii before age 2 years, but most infections are asymptomatic. Symptomatic children are generally immunocompromised. PJP commonly presents with nonproductive cough, tachypnea, dyspnea, fever, and hypoxia. The presentation can be acute or subacute depending on the underlying etiology. Pediatric patients who are predisposed to PJP include patients with HIV infection, underlying malignancy, primary immunodeficiency, or severe malnutrition or organ transplant recipients on immunosuppressive therapy.7 These underlying risk factors should be considered and investigated in any patient presenting with PJP.
Initially, no predisposing cause could be found for our patient. Congenital immunodeficiency syndromes associated with PJP are those where T-cell populations are affected. In one retrospective study of patients with PJP, associated immunodeficiencies included Wiscott-Aldrich, severe combined immunodeficiency, hyper IgM, and 1-Stat5b deficiency. Our patient was tested for all of these, resulting in a negative workup.
At 12 months of age, the patient developed a more classic symptom of CGD, and the diagnosis was pursued. CGD is characterized by the inability of neutrophils and monocytes to eradicate catalase-positive microorganisms8,9 This is generally because of a defect in respiratory burst causing the failure to generate reactive microbial oxygen metabolites and hydrogen peroxide. The majority of cases are X-linked recessive, whereas a minority are autosomal recessive. Clinical presentations of CGD are highly variable. Children can present with recurrent infections or atypical pneumonia and/or lymphadenitis and poor wound healing, as in the case of our patient. Other presentations include hepatic abscesses and/or other abscesses, osteomyelitis, and other atypical or severe infections due to bacteria or fungi. CGD patients also have inflammatory syndromes associated with granulomatous disease in the viscera that can cause mass effect and obstruction. In retrospect, the patient did have hypoechoic splenic structures that may have been granulomas associated with CGD. However, because the patient improved with therapy directed against P jirovecii, invasive measures to diagnose these structures were not pursued. Family history of infections can be an important part of the history. This patient did not have any family history of recurrent or unusual infections. Although the most common organisms involved are catalase-positive organisms, such as S aureus, Burkholderia cepacia, Serratia marcescens, Listeria species, Escherichia coli, and fungal pathogens such as Aspergillus fumigatus, Candida glabrata, and Candida albicans, various other organisms have been associated with infections in CGD patients, including P jirovecii.8–10 Currently our patient is doing well on recommended management of CGD involving the use of interferon-γ and prophylactic antifungal agents/antibiotics. At this time, the only known cure for CGD is hematopoietic stem cell transplantation.11
Dr Padilla led the initial writing of the manuscript, recruited various specialists for writing the manuscript, revised the manuscript, and was involved in the care of the patient; Dr Logan contributed to the writing of the manuscript, critically revised all versions of the manuscript, and was involved in the care of the patient; Dr Codispoti contributed to the writing of the manuscript, revised the manuscript, and was involved in the care of the patient; Dr Jones contributed to the writing of the manuscript and was involved in the care of the patient; Dr Van Opstal led the writing of the final manuscript, revised the manuscript, and was involved in the care of the patient; and all authors approved the final manuscript as submitted.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Dr Logan acknowledges support from the National Institutes of Health (NIH) award number 1K08AI112506-01 and The Children’s Foundation. Funded by the National Institutes of Health (NIH).
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.