Pediatric Cough: Just Another Virus?

The Case

The patient was a 2-year-old female who had been taking amoxicillin for 8 days for an otitis media. She was brought in by her mother for a recurrence of fever, the development of cough, and increased work of breathing. The mother stated that four days ago, the child started to again spike fevers “over 100” and seemed to be having increased lethargy and decreased appetite. The patient’s vital signs revealed that she was febrile to 102F, tachycardic, and normotensive. On exam, the child was well appearing and in no acute distress. Auscultation to the lungs revealed decreased breath sounds throughout the right hemithorax and mild subcostal retractions. A two-view chest X-ray was obtained for further evaluation.

 Figure       SEQ Figure \* ARABIC
   1:       Chest X-ray demonstrating opacification of right hemithorax with foci of gas and air fluid levels

Figure 1: Chest X-ray demonstrating opacification of right hemithorax with foci of gas and air fluid levels

Diagnosis

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   2:       Pulmonary ultrasound demonstrating consolidation of lung tissue and loculated pleural effusion

Figure 2: Pulmonary ultrasound demonstrating consolidation of lung tissue and loculated pleural effusion

The patient’s X-ray showed near complete opacification of the right hemithorax with a small amount of mediastinal shift to the left. Additionally, there were small foci of gas at the right lung base and a larger collection of gas at the right lung apex with an air-fluid level.

In light of these findings, radiology recommended an ultrasound of the right lung to further characterize the disease process. The ultrasound demonstrated a large volume of loculated fluid in the right hemithorax and mobile gas within the pleural space. 

With the findings from both the chest X-ray and the lung ultrasound, the definitive diagnosis of necrotizing pneumonia with empyema and bronchopulmonary fistula was made.

Necrotizing Pneumonia

First identified in adults and later in children, necrotizing pneumonia is a rare, but serious complication of community acquired pneumonia (1). As the name suggests, the disease process involves destruction and necrosis of pulmonary tissue. It is thought that this significant tissue damage is caused by thrombosis of intrapulmonary vessels. This reduced blood flow not only leads to loss of pulmonary tissue, but also results in a reduction in local antibiotic concentration. The decrease in antibiotic penetrance allows for the active infection to flourish (2).

Since first being described in children in 1994, the rates of culture and pathologic proven necrotizing pneumonia are slowly increasing (1). Current reports indicate that necrotizing pneumonia may complicate around 4% of community acquired pneumonias (3) and up to 20% of pneumonias associated with empyema (4). It is thought that this increase is partly due to an increased awareness of the disease process, but also from changes in organisms and in antibiotic prescribing patterns (5). Of the reported cases of necrotizing pneumonia in literature, a majority have been caused by S. pneumoniae or S.aureus (1).  

Clinical Features

The clinical features of necrotizing pneumonia are nearly indistinguishable from those of community acquired pneumonia. Children often present with fever, cough, tachypnea, tachycardia, chest pain, and focal pulmonary findings on physical exam. Of the reported cases, a majority of children had been previously healthy without any significant co-morbid conditions (6). Often, children had been appropriately treated for community acquired pneumonia with outpatient antibiotic therapy, but re-presented with worsening or persistent symptoms (7).

Diagnostic Workup

There should be a high level of suspicion for necrotizing pneumonia for any child who remains unwell despite appropriate antibiotic treatment for community acquired pneumonia. Appropriate treatment most commonly being amoxicillin. Laboratory evaluation often shows an elevation in white blood cell count, elevation in C-reactive protein, hypoalbuminemia, and anemia (1). Additionally, patients who appear to be decompensating may demonstrate signs of septic shock such as a lactic acidosis and end-organ damage. As such, an infectious work-up is recommended including CBC, BMP, Lactic acid, VBG, CRP, and blood cultures.

Chest X-ray is often used as first-line for radiographic evaluation for necrotizing pneumonia and may reveal airspace opacity, gas foci, air-fluid levels, and mediastinal shift from mass effect. However, chest X-ray has poor sensitivity, particularly early in the disease course, as areas of necrosis are fluid filled and often have similar density to that of surrounding lung tissue. It is believed that for this reason, chest x-ray is only diagnostic in 27-41% of children with necrotizing pneumonia (1).

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   3       Representative CT chest demonstrating cavitary lesions within an area of consolidation.   Case  courtesy of Dr Sakher  Alkhaderi on  Radiopaedia.org

Figure 3 Representative CT chest demonstrating cavitary lesions within an area of consolidation.

Case courtesy of Dr Sakher  Alkhaderi on Radiopaedia.org

Given the poor performance of chest x-ray in the diagnosis of necrotizing pneumonia, contrast enhanced computed tomography (CT) has become the standard in diagnosing necrotizing pneumonia. With CT imaging of the chest, loss of vascularity, destruction of pulmonary tissue, and cavitary formation can be assessed. All of these findings are hallmark for necrotizing pneumonia (8).

Despite the increased sensitivity of CT, challenges exist in the pediatric population as patients are often unable to tolerate CT or are too sick to travel to radiology. For these reasons, pulmonary ultrasound has been studied in pneumonia and has been found to reliably detect lung consolidation (9). In a study in children with necrotizing pneumonia, doppler ultrasound was used to assess for lung hypoperfusion and was found to correlate well with CT scan results (10). For these reasons, lung ultrasound can be used to detect the consolidation found in community acquired pneumonia as well as the additional features of necrotizing pneumonia such as effusion, hypoechoic cavitary lesions, and decreased regional pulmonary perfusion. Challenges that exists with ultrasound are that it may not be available at all institutions and is highly dependent on operator skill level and comfort with pediatric patients.

Treatment

Once the diagnosis of necrotizing pneumonia has been made, prompt treatment is warranted. Broad spectrum IV antibiotics should be initiated and selection of antibiotic should be based on local antibiogram and organism prevalence data. One suggested antibiotic regimen consists of ceftriaxone or cefotaxime plus clindamycin. At minimum, antibiotic selection should include coverage against gram positive organisms (11). As with all severe infections, antibiotics should be narrowed whenever possible on the basis of culture data.

Surgical intervention is not always warranted as invasive management can cause in an increase in bronchopulmonary fistula formation (12). However, if the initial workup reveals signs of mass effect, such as mediastinal shift, or evidence of loculated empyema, surgical consultation and debridement is required. Very often, video-assisted thoracoscopic surgery (VATS) is necessary for definitive management, but it has been suggested that chest tube drainage alone may suffice in cases of non-loculated parapneumonic effusions (1). Surgical intervention has the added benefit of being able to collect reliable culture data.

Case Conclusion

With the diagnosis of necrotizing pneumonia, the patient was started on vancomycin and ceftriaxone for broad antibiotic coverage. Pediatric surgery was consulted and determined that the patient would benefit from a VATS procedure. The patient was taken to the OR where a VATS was performed and two chest tubes were placed. Cultures were taken during the procedure and grew MRSA. The patient had an overall hospital stay of 8 days, during which the chest tubes were removed, and she was discharged with an extended course of clindamycin and infectious disease follow-up.  

Faculty Reviewer: Dr. Jane Preotle

References

1. Masters LB, Isles AF, Grimwood K. Necrotizing pneumonia: An emerging problem in children? Pneumonia. 2017;9:(11)epub.

2. Chatha N, Fortin D, Bosma KJ. Management of necrotizing pneumonia and pulmonary gangrene: a case series and review of the literature. Can Respir J. 2014;21:239-245.

3. Nicolaou E, Bartlett A. Necrotizing Pneumonia. Pediatric Annals. 2017; 46(2)e65-e68.

4. Ramphul N, Eastham KM, Freeman R, Eltringham G, Kearns AM, Leeming JP, et al. Cavitatory lung disease complicating empyema in children. Pediatr Pulmonol. 2006;41:750–753.

5. Spencer DA, Thomas MF. Necrotising pneumonia in children. Paediatr Respir Rev. 2014;15:240-245

6. Bender JM, Ampofo K, Korgenski K, Daly J, Pavia AT, Mason EO, et al. Pneumococcal necrotizing pneumonia in Utah: does serotype matter? Clin Infect Dis. 2008;46:1346-1352.

7. Fretzayas A, Moustaki M, Alexopoulou E, Nychtari G, Nicolaidou P, Priftis KN. Clinical notations on bacteraemic cavitating pneumococcal pneumonia in nonvaccinated immunocompetent children. J Trop Pediatr. 2009;55:257-261.

8. Hodina M, Hanquinet S, Cotting J, Schnyder P, Gudinchet E. Imaging of cavitary necrosis in complicated childhood pneumonia. Eur Radiol. 2002;12:391-396.

9. Shah VP, Tunik MG, Tsung JW. Prospective evaluation of point-of-care ultrasonography for the diagnosis of pneumonia in children and young adults. JAMA Pediatr. 2013;167:119-125.

10. Lai SH, Wong KS, Liao SL. Value of lung ultrasonography in the diagnosis and outcome prediction of pediatric community-acquired pneumonia with necrotizing change. PLoS One 2015;10(6)epub

11. Islam S, Calkins CM, Goldin AB, et al. The diagnosis and management of empyema in children: a comprehensive review from the APSA outcomes and clinical trial committee. J Pediatr Surg. 2012;47:2101-2110.

12. Hoffer FA, Bloom DA, Colin AA, Fishman SJ. Lung abscess versus necrotizing pneumonia: implications for interventional therapy. Pediatr Radiol. 1999;29:87-91.

 

Digging Deeper for Musculoskeletal Pain

THE CASE

A 6 y/o male with PMHx of asthma presents to the ED with bilateral leg pain, back pain, and chills for one day. Per his mother, he awoke earlier in the morning complaining of pain and chills that was initially responsive to ibuprofen, but then recurred later that morning with a refusal to ambulate because of the pain. Of note, that patient was in a potato sack race the day before and had fallen onto both legs, but was ambulatory following his fall and was otherwise acting at his baseline yesterday. His mother notes that he has been having intermittent back pain for the last several weeks. He denies fevers, congestion, vomiting, diarrhea, bleeding, bruising, or tick exposures.

On exam, the patient is well-appearing and interactive, and his musculoskeletal exam is notable for mild tenderness of the medial aspect of his right distal lower extremity without any deformities, joint swelling, or erythema. He also has para-spinal lumbar muscle tenderness, but no midline spinal tenderness. He has full strength of his lower extremities while laying down and symmetric sensation to light touch; however, when the patient is asked to ambulate, he avoids weight bearing on the right leg due to pain and a limping gait.

Plain films are ordered that show a possible buckle fracture of his proximal 3rd metatarsal of the right foot, but the patient denies any point tenderness. Lumbar spine films are normal. Because his symptoms of chills and intermittent back pain did not seem consistent with a foot fracture, additional labs are ordered including CBC, inflammatory markers, and an LDH.

While his workup is pending, the patient spikes a fever to 101.2F and cultures were added. Preliminary lab work is notable for a leukocytosis to 29.7, hemoglobin of 9.7, CRP 24, and ESR of 104. His LDH was significantly elevated to 2360. Given concern for possible malignancy, heme-onc is consulted, and a manual differential performed by pathology reveals 65% blasts concerning for acute lymphoblastic leukemia (ALL). The patient was started on cefepime for his fever and D5 fluids and admitted to heme-onc.

Further inpatient testing confirms the diagnosis of pre-B cell ALL, and the patient is started on chemotherapy. On hospital day #24, he demonstrates good neutrophil recovery and was discharged home with close outpatient follow-up.

DISCUSSION

Acute Lymphoblastic Leukemia (ALL)

ALL is a malignant disease of lymphoid precursor cells in the bone marrow, and is the most common malignancy among children, comprising 30% of pediatric cancers.

Although typical symptoms include easy bleeding or bruising, fever, pallor, and fatigue, musculoskeletal (MSK) complaints as presenting symptoms are reported in 20-38% of patients. (1,2) These include bone pain, joint pain, limping gait, or back pain that can often be confused with orthopedic or rheumatologic conditions and lead to a delay in diagnosis. (3,4)

Back-up—back pain in pediatrics?

Classically, lower back pain (LBP) in the pediatric population has been thought of as a “red flag” because its perceived low prevalence and earlier studies demonstrating a high rate of identifiable and often serious underlying pathology. (6) However, recent literature has challenged this notion, demonstrating that LBP in the pediatric population is of increasing prevalence, is mostly MSK in nature and self-limiting, and nearly 80% of patients have no specific underlying etiology despite advanced testing. (7-9) However, the differential for back pain in the pediatric population is broad, and infectious, inflammatory, and malignant etiologies should also be considered. For a review and algorithmic approach to back pain in pediatrics, check out this AAFP summary.

When to consider malignancy?

Malignancy should always be considered in patients who presents with rheumatic complaints; however, history and physical exam are of the utmost importance in leading to the correct diagnosis. Typical findings can include lymphadenopathy, hepatosplenomegaly, pallor, petechiae, or ecchymosis. Care should be taken to identify any possible “red-flag” signs or symptoms such as those listed below:

  • Fevers
  • Night sweats
  • Weight loss
  • Constant pain despite NSAIDS
  • Pain that awakens child or night pain
  • Non-articular pain
  • Pain disproportionate to exam
  • Abnormal neurologic findings (1,10,11)

These findings should prompt further workup including blood work, plain films, and advanced imaging as indicated. The most common findings on labs are anemia, thrombocytopenia, the presence of lymphoblasts, elevated inflammatory markers, and elevated LDH. However, initial blood work may be normal, so if clinical suspicion is high, further diagnostic testing may be warranted.

What’s up with that Lactate Dehydrogenase elevation (LDH)?

LDH is a cytoplasmic enzyme that exists in most tissues, and can be a marker of tissue damage, hemolysis, or high cell turnover. In our case, the patient was noted to have a significantly elevated LDH, but no clear evidence of hemolysis on his lab work. In a study of adult inpatients looking at LDH as a distinguishing biomarker, patients with significantly elevated LDH >800 IU/ml were strongly associated with the presence of underlying cancer, metastases, and infection. (12) So the next time you see a significantly elevated LDH, consider underlying malignant or infectious disease.

Summary

  • ALL is the most common malignancy of children.
  • Typical features are fevers, fatigue, pallor, bleeding or bruising.
  • MSK pain can be a common presenting complaint in ALL making it difficult to diagnose.
  • Back pain is actually more common in pediatrics than previously thought and often benign unless associated with red-flag symptoms.
  • Obtain blood work including CBC, inflammatory markers, LDH, and plain films if suspicion for serious underlying pathology is high.
  • Significantly elevated LDH may be a marker of malignancy or infection.

Faculty Reviewer: Jane Preotle, M.D.

Sources

1 Zombori L, Kovacs G, Csoka M, et al. Rheumatic symptoms in childhood leukaemia and lymphoma—a ten year retrospective study. Pediatr Rheumatol. 2013;11:20.

2 Sinigaglia R, Gigante C, Bisinella G, et al. Musculoskeletal manifestations in pediatric acute leukemia. J Pediatr Orthop. 2008;28(1):20-8.

3 Kobayashi D, Satsuma S, Kamegaya M, et al. Musculoskeletal conditions of acute leukemia and malignant lymphoma in children. J Pediatr Orthop. 2005;14:156-161.

4 Cabral DA, Tucker LB. Malignancies in children who initially presents with rheumatic complaints. J Pediatr. 1999;134(1):53-7.

5 Kang S, Im HJ, Bae K, et al. Infuence of muscuoskeletal manifestations as the only presenting symptoms in B-cell Acute Lymphoblastic Leukemia. J Pediatr. 2017;182:290-295.

6 Turner PG, Hancock PG, Green JH, et al. Back pain in childhood. Spine. 1989;14:812-14.

7 MacDonald J, Stuart E, Rodenberg R. Musculoskeletal low back pain in school-aged children: A review. JAMA Pediatr. 2017;171(3):280-287.

8 Bhatia NN, Chow G, Timon SJ, et al. Diagnostic modalities for the evaluation of pediatric back pain: a prospective study. J Pediatr Orthop. 2008;28(2):230-3.

9 Yang S, Werner BC, Singla A, Abel MF. Low back pain in adolescents: a 1-year analysis of eventual diagnosis. J Pediatr Orthop. 2017;37(5):344-47.

10 Massoud M, Del Bufalo F, Caterina Musolino AM, et al. Myeloid sarcoma presenting as low back pain in the pediatric emergency department. J Emerg Med. 2016;51(3):308-14.

11 Feldman DS, Straight JJ, Badra MI, et al. Evaluation of an algorithmic approach to pediatric back pain. J Pedaitr Orthop. 2006;26:353-8.

12 Erez A, Shental O, Tchebiner JZ, et al. Diagnostic and prognostic value or very high serum lactate dehydrogenase in admitted medical patients. Isr Med Assoc J. 2014;16(7):439-43.

 

Tales from LBJ Tropical Medical Center, Weil's Disease: A Curly Conundrum

This is case from the Lyndon B. Johnson Medical Center in American Samoa:

A 46 year old healthy male presented with a “flu-like illness.” He reports three days of headache, myalgias, nausea, vomiting, fevers, and chills. No other associated symptoms. His children have been sick with “the flu,” so he suspects he likely has the same. 

Vitals:

HR: 107 BP: 137/42 SpO2: 99% on RA RR: 15 T: 100.7

Physical Examination:

Gen: Well appearing male of stated age
HEENT: NCAT. Conjunctival suffusion. Sinuses non-tender. TMs and OP are clear. No LAD. MMM.
Neck: Supple. Full ROM.
Heart: Tachycardic and regular rhythm. No murmurs, rubs, or gallops.
Lungs: Clear to auscultation bilaterally. No respiratory distress.
Abdomen: Soft, non-tender. No rebound, guarding, or distention.
Neuro: Alert and orientated x 4. Moving all extremities.
Skin: Warm and dry. No rash.

 Figure 1: Conjunctival suffusion. Source: American Journal of Tropical Medicine and Hygiene, 2012.

Figure 1: Conjunctival suffusion. Source: American Journal of Tropical Medicine and Hygiene, 2012.

Given concern for possible dengue fever and/or leptospirosis, CBC and CMP were sent and remarkable for a mild transaminitis and thrombocytopenia. Confirmation testing for dengue fever and leptospirosis was not available. Given the patient’s clinical findings of conjunctival suffusion and his constellation of symptoms, the patient was treated empirically for presumed leptospirosis with oral doxycycline. The patient was discharged from the ED with a plan to return two days later for follow up and a repeat CBC. At that time, he reported complete resolution in his symptoms, with resolution in his laboratory aberrancies.



Diagnosis: Weil’s Disease, aka leptospirosis

Epidemiology:

  • Widespread zoonotic infection found in both temperate and tropical climates, although there is a 10 times higher prevalence in the tropics.
  • Etiology is secondary to infection by bacterium of the genus Leptospira, a spirochete. 
  • WHO models suggest about 873,000 cases worldwide annually with around 48,600 deaths, although this estimation is difficult to make due to under-reporting of the disease.
  • Incidence is low in the US, with Hawaii reporting the most cases. In the tropics, the disease is prevalent/endemic in areas of poverty (poor housing and sanitation, subsistence living), and often peaks after large amounts of rainfall and flooding.
  • Found in a variety of animals, although rodents are the most important reservoirs in terms of transmission of the disease. Rodents shed the organism intermittently in their urine throughout their lifetime, infecting soil and sources of fresh water. The spirochete can stay alive in the environment for days to months.
  • Human infection is through exposure to animal urine or contaminated environment (soil and water).
  • Consider the disease in patients traveling from high risk areas of the world.
 Figure 2: Prevalence of leptospirosis in 2015 on a gradient from white (0-3 cases per year) to red (>100 cases per year). Source: Yale News, 2015.

Figure 2: Prevalence of leptospirosis in 2015 on a gradient from white (0-3 cases per year) to red (>100 cases per year). Source: Yale News, 2015.

Clinical Features:

  • Broad spectrum of clinical presentation, from mild, self-limited disease to severe and life-threatening disease.
  • Average incubation period after inoculation is about 10 days.
  • Abrupt onset of fevers, rigors, myalgias, and headache or “flu-like” syndrome; 75-100% of patients present with these symptoms. 
  • Conjunctival suffusion is often an overlooked clinically important finding. One case series suggests that it occurs in over half of patients with leptospirosis. It is not a common finding in other infectious diseases. Conjunctival suffusion should raise a clinician’s suspicion for leptospirosis in an otherwise non-specific febrile illness.
  • Less common findings include non-productive cough, nausea, vomiting, diarrhea, sore throat, lymphadenopathy, hepatosplenomegaly, and skin rash. These symptoms are seen in 30-50% of patients.
  • Biphasic illness with a “bacterial” and “immunologic” phase, often overlapping.
  • Complications include acute renal failure and jaundice, pulmonary hemorrhage, ARDS, uveitis, myocarditis, rhabdomyolysis, and multiorgan failure. The presence of ARF and jaundice in leptospirosis constitutes Weil’s Disease. Most fatalities are secondary to ARDS and multi-organ failure.
  • Renal failure is often associated with hypokalemia and is non-oliguric. Patients may require renal replacement therapy. There is often full recovery of both renal and liver function with appropriate treatment.
  • Based on one retrospective case-study, severe disease seemed to be associated with delayed antibiotic administration (greater than 2 days from initiation of symptoms) and infection due to the Leptospira interrogans serogroup.
  • Laboratory findings are generally non-specific and include a normal white count (although a left shift might be seen), thrombocytopenia, hyponatremia, hypokalemia, elevated CK, and transaminitis (AST and ALT <200 IU/L, although significant hyperbilirubinemia of 60-80 mg/dL). 
  • Sterile pyuria and CSF pleocytosis, evidence of the immunologic phase of the disease.
  • Chest x-ray may demonstrate small, nodular opacities. This is thought to represent alveolar hemorrhage or pulmonary edema, which portends a poorer outcome.
  • Differential diagnosis includes malaria, dengue, chikungunya, typhoid fever, rickettsial disease, hantavirus infection, influenza, ehrlichiosis, and viral illness
 Figure 3: The spirochetes of the genus Leptospira. Source: Health and Fitness Tips Blog, 2012.

Figure 3: The spirochetes of the genus Leptospira. Source: Health and Fitness Tips Blog, 2012.

Diagnosis and Treatment:

  • High index of suspicion is required and should be based on epidemiological exposure and clinical symptoms, especially given the non-specificity of laboratory and clinical findings.
  • Serological testing is available, including ELISA testing, PCR, and cultures. ELISA diagnostic performing is considered variable in endemic regions, however PCR is becoming more available, and providing more accurate and timely diagnoses. Blood cultures are insensitive and typically only positive during the first 10 days of illness. Urine cultures can be positive for up to 30 days after symptom resolution.
  • Empiric treatment is recommended in the setting of high clinical suspicion and in the absence of diagnostic testing.
  • Antimicrobial treatment reduces duration of illness and shedding of the organism in the urine.
  • Outpatient treatment is acceptable for minor illness, while inpatient treatment is reserved for those with severe disease. Oral doxycycline or azithromycin is recommended for outpatient treatment while IV penicillin/cephalosporin or doxycycline is recommended for inpatient treatment (with doxycycline only if rickettsial disease cannot be ruled out).
  • Can consider prophylaxis with doxycycline if traveling to an endemic area with a high likelihood for exposure.

“No one dies here without a dose of doxycycline” –Dr. Judith Fitzgerald, Hilo Medical Center, Hilo, Hawaii.

References:

1: Lin CY, Chiu NC, Lee CM. Leptospirosis after Typhoon. American Journal of Tropical Medicine and Hygiene. 2012. 

2: Mahmood F. What is Leptospirosis. Health and Fitness Tips. November, 2012. <http://daily-healthinformation.blogspot.com/>.

3: Greenwood, M. Global burden of leptospirosis is greater than previously thought, and growing. Yale News. September, 2015. <https://news.yale.edu/2015/09/17/global-burden-leptospirosis-greater-thought-and-growing>.

4: Speer, B. Introduction to Spirochetes. 1994. <http://www.ucmp.berkeley.edu/bacteria/spirochetes.html>.

5: Day, N. Treatment and Prevention of Leptospirosis. UptoDate. March, 2017.

6: Day, N. Epidemiology, microbiology, clinical manifestations, and diagnosis of leptospirosis. UptoDate. November, 2017.

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