Case Report: Typhoid Fever Complicated by Acute Respiratory Distress Syndrome in a Pediatric Traveler

Abstract.

Acute respiratory distress syndrome (ARDS) is seldom described as a complication of typhoid fever (TF). Only 13 cases have hitherto been reported in the English and non-English literature since 1990. We report an 8-year-old boy with TF after return from India who developed pediatric ARDS (pARDS) despite adequate antibiotic treatment. Among patients with available information including this case, we noted that most not born or raised in a TF-endemic country (4/5) compared with one (1/6) of the domestic cases in a TF-endemic country developed ARDS within 48-72 hours of starting the antibiotic treatment. Our case raises important questions regarding the frequency, pathophysiology, and appropriate management of ARDS and pARDS in patients with TF.

INTRODUCTION

Typhoid fever (TF) is an important cause of morbidity and mortality in resource-limited countries, with an estimated 12–22 million cases and 130,000–225,000 deaths annually.¹ A severe or fatal disease course is marked by gastrointestinal bleeding, intestinal perforation, myocarditis, pneumonia, toxic encephalopathy, or shock.² Acute respiratory distress syndrome (ARDS) is a scarcely reported severe complication of TF. We report a case of TF complicated by pediatric ARDS (pARDS) in a child traveler and summarize all previous TF-related ARDS cases reported in the literature. Given the age group-specific diagnostic criteria, we describe pARDS separately from adult ARDS cases.^3,4

CASE

A previously healthy 8-year-old male presented with 7 days of fever, cough, and 2-day history of watery diarrhea, vomiting, and diffuse abdominal pain. He had returned from travel to India a month before presentation. Physical examination revealed a moderately distressed child with fever (38.3°C), tachycardia (165 beats per minute), a wide pulse pressure (111/45 mmHg), and distended abdomen with mild diffuse tenderness. The remainder of his physical examination was unremarkable. Laboratory investigations were notable for a white blood cell count of 6,870/mm³ (neutrophils, 78%; bands, 4%; and lymphocytes, 16%), a platelet count of 120,000/mm³, a serum creatinine level of 0.4 mg/dL, an aspartate aminotransferase level of 90 U/L, an alanine aminotransferase level of 70 U/L, a serum albumin level of 3.6 g/dL, a total bilirubin of 0.4 mg/dL, an erythrocyte sedimentation rate of 54 mm/hour, and a C-reactive protein of 303 mg/L. A computed tomography scan of the abdomen showed enlarged ileocolic lymph nodes. He was admitted for dehydration due to profuse watery diarrhea. The blood culture indicated bacterial growth at 12 hours of incubation and treatment with ceftriaxone was empirically started. Salmonella enterica subspecies enterica serovar Typhi (S. Typhi) was eventually isolated with resistance to fluoroquinolones and sensitivity to ceftriaxone and azithromycin.

Overnight, the patient remained febrile (maximal temperature 39.1°C), became hypotensive (90/50 mmHg), and developed respiratory distress (respiratory rate, 55/minute; O₂ saturation of 85%). A chest radiograph (CR) showed new bilateral pulmonary infiltrates. Because of lack of improvement after administration of fluid boluses and supplemental oxygen, the patient was transferred to the pediatric intensive care unit for septic shock management and ventilator support. Here, the patient was placed on noninvasive positive airway pressure ventilation (NPPV) and required 40% FiO₂. With an S_pO2/F_IO2 ratio < 264, he met the criteria for diagnosis of pARDS per the Pediatric Acute Lung Injury Consensus Conference (PALICC) definition.³ Two days later, while still on NPPV, the patient showed signs of worsening respiratory distress requiring endotracheal intubation and mechanical ventilation. A repeat CR after intubation revealed increased bilateral opacities and new-onset pleural effusions requiring the placement of bilateral chest tubes. Workup of the pleural fluid revealed 1,000 RBCs, < 30 total nucleated cells, negative Gram stain, and sterile culture. A decreased serum albumin level of 1.9 g/dL may have contributed to the development of the pleural effusions. Azithromycin was added at this time to the antibiotic regimen.

The patient responded favorably with successful extubation to room air on hospital day 9. Subsequently, he developed altered mental status for 3 days. A magnetic resonance imaging scan of the brain was unremarkable; a lumbar puncture had not been performed as the change in conscious level was attributed to narcotic withdrawal. The patient’s clinical and mental status continued to improve for 10 days until defervescence. He completed a 14-day course of ceftriaxone with azithromycin and was discharged fully recovered after 19 days of hospitalization.

A literature search was completed using PubMed with the search terms “Typhoid Fever” and “Acute Respiratory Distress Syndrome.” References within articles were reviewed for additional cases and were limited to ARDS caused by S. Typhi in humans. In total, we identified 13 previous cases (two children and 11 adults) of TF-related ARDS in the English and non-English literature between 1990 and 2016 (Table 1).^5–17

Table 1.

Demographic and clinical characteristics of typhoid fever cases complicated by ARDS/pARDS reported in the literature, including the presented case

Age (years)	Gender	Days of symptoms before presentation	Country where case diagnosed	Destination of recent travel	Naïve†	Clinical manifestations at presentation	Initial antibiotic treatment	Additional antibiotics used after onset of ARDS	Duration of therapy until ARDS (days)	Outcome
Pediatric Cases
8*	M	7	USA	India	Yes	Fever, cough, diarrhea, vomiting, and abdominal pain	Ceftriaxone	Azithromycin	2	Recovered
165	M	2	USA	None	Yes	Fever, abdominal pain, and diarrhea	Ceftriaxone + ciprofloxacin	TMP/SMX + dexamethasone	2	Recovered
156	F	7	India	None	No	Fever, diarrhea, abdominal pain, and hepatosplenomegaly	Ciprofloxacin + amikacin + metronidazole	None	5	Recovered
Adult Cases
477	F	14	India	None	No	Fever, arthritis, headache, abdominal pain, vomiting, and anorexia	Ceftriaxone	Azithromycin	5	Recovered
NR8	F	NR	India	NR	NR	Fever	NR	NR	NR	Recovered
379	F	10	Japan	Bangladesh	Yes	Fever and abdominal pain	Doripenem/ceftriaxone	Moxifloxacin	2-3	Recovered
2510	M	14	USA	Haiti	Yes	Fever, vomiting, diarrhea, dark urine, and dyspnea	Ceftriaxone	Ampicillin + chloroquine phosphate + doxycycline	2–3	Recovered
3411	F	NR	Philippines	NR	No	Sepsis syndrome and pneumonia	Ceftriaxone + piperacillin—tazocin	NR	NR	Died
2312	M	7	Canada	Philippines	No	Fever, nausea, vomiting, chills, diarrhea, jaundice, and splenomegaly	Ampicillin + chloramphenicol	None	∼7	Recovered
2513	F	18	Sri Lanka	None	No	Fever, cough, headache, diarrhea, and splenomegaly	Chloramphenicol + ceftazidime	None	8	Died
1914	F	NR	South Africa	None	No	Fever, altered mental status, and diarrhea	(Cefazolin + ampicillin)/ceftriaxone + metronidazole + amikacin	None	∼3	Died
4015	M	31	Japan	Singapore + Indonesia	Yes	Fever, fatigue, and diarrhea	Thiamphenicol + gentamycin + chloramphenicol + ampicillin + cefoperazone	None	15	Recovered
2616	M	14	Israel	None	No	Fever, abdominal pain, diarrhea, splenomegaly, and bilateral basilar crackles	Erythromycin + ampicillin	Chloramphenicol	8	Recovered
NR17	NR	NR	Netherlands	NR	NR	NR	NR	NR	NR	NR

ARDS = acute respiratory distress syndrome; F = female; M = male; NR = not recorded; pARDS = pediatric ARDS; TMP/SMX = trimethoprim/sulfamethoxazole.

* Present case.

† Defined as case report providing adequate information to confirm patient was born or raised in nonendemic country.

DISCUSSION

Typhoid fever is a rare disease in wealthy countries. In the United States, approximately 300–400 culture-confirmed cases are reported to the CDC annually; most cases are imported with highest risk among travelers visiting friends and relatives in the Indian subcontinent.² Typhoid fever disproportionately infects children in endemic areas. In one U.S. study, up to 41% of reported cases were among children < 18 years of age.² Clinical features of TF in children are usually nonspecific and fever frequently is the main manifestation presenting as a fever of unknown origin.¹⁸ Severe TF is noted for its significant gastrointestinal, neurologic, and cardiac involvement. Although cough may indicate respiratory involvement among children with TF in endemic regions, respiratory complications such as pleural effusion, empyema, and bronchopleural fistulas are rare and more commonly observed in patients with underlying lung abnormalities or various causes of immunosuppression.¹⁸ Acute respiratory distress syndrome has not been noted as part of the spectrum of severe TF in literature reviews on extraintestinal complications of TF and has hitherto only been described in isolated case reports.^5–19

The diagnosis of ARDS is resource-intensive, suggesting that the occurrence of ARDS in TF in low-income countries has been under-recognized and under-reported.⁴ Among wealthy countries, the diagnosis of ARDS may also be challenging. In an observational study of 459 intensive care units across 50 countries, 40% of all cases of ARDS were undiagnosed.²⁰ In ARDS, injury to pneumocytes and pulmonary endothelium leads to a dysregulated inflammatory response in the lung that subsequently develops into severe hypoxemic respiratory failure. Causes of ARDS can include pneumonia, sepsis, gastric aspiration, drowning, and trauma. Recently, the diagnosis of pARDS was established with the 2017 PALICC definition criteria, created to aid in the discrepancy in epidemiology and outcomes for pediatric patients observed while using the Berlin definition intended for adults.^3,21 Children and infants are prone to more severe respiratory insults that stem from anatomic and physiological differences. Also, because arterial lines are less commonly used in children and infants, the PALICC definition permits the use of oxygen saturation index in the diagnosis of pARDS. In addition, the PALICC definition only requires unilateral, in contrast to bilateral, pulmonary disease on chest imaging; both modifications are to aid in earlier recognition and earlier intervention of the syndrome.

Our pediatric traveler returning from a TF-endemic area presented with many features of acute noncomplicated TF; only his abdominal pain and profuse diarrhea indicated severe disease which warranted admission. Despite proper empiric treatment, his disease course acutely worsened with new-onset respiratory distress and progression to pARDS. Likewise, the two other pediatric cases discovered in the literature presented with gastrointestinal complaints, yet only our patient had additional respiratory involvement (Table 1). Of note, of the pediatric cases, only our case was travel-related, whereas the other two children had acquired the infection domestically. Among the nine of 11 reported adult TF-related ARDS cases that had recorded data on age and gender, there was a female predominance with a median age of 26 years (Table 2). Half of patients were travelers, and three of nine were born or raised in an S. Typhi nonendemic country, and hence categorized as naïve to S. Typhi. All presented with fever, most (8/10) had gastrointestinal complaints, and more than a third (4/10) had additional respiratory involvement (Table 1). Most adult patients (5/9) had additional ARDS risk factors, that is, surgery, disseminated intravascular coagulation, and pneumonia, and a third (3/10) died. All patients had been receiving antibiotic treatment for TF before the development of ARDS. Within the pediatric cases, pARDS was established within 48 hours of antibiotic treatment in both likely naïve cases in the United States, whereas the reported domestic case from India presented on the fifth day of treatment. Likewise, two of Three adult naïve cases observed onset of ARDS within <48-72 hours of therapy (Table 2).^9,10 The lack of immune tolerance in naïve hosts in a nonendemic country such as the United States may have allowed a larger and faster inflammatory response after the initiation of effective antibiotic treatment, explaining the relatively more rapid onset of ARDS. Similar observations of ARDS occurring after treatment initiation were recognized in another intracellular parasite, Babesia sp.²² Extracellular release of organisms previously undetected by the immune system may cause sudden sensitization that underlies the development of ARDS. Alternatively, failure of empiric treatment leading to a severe disease course that progresses to ARDS is unlikely. In all cases including ours, all strains of S. Typhi were sensitive to antibiotic treatment leading to rapid sterilization of cultures.

Table 2.

Comparison of adult versus pediatric typhoid fever cases complicated by ARDS reported in the literature including the presented case

Characteristics	Adult (N = 11)	Pediatric (N = 3)
Gender, n (%)
Female	6/10 (60)	1/3 (33)
Male	4/10 (40)	2/3 (66)
Median age (years; range)	26 (19–47)	15 (8–16)
Traveler, n (%)	4/8 (50)	1/3 (33)
Naïve patient,* n (%)	3/9 (33)	2/3 (66)
ARDS risk factors,† n (%)
Naïve	2/3 (66)	0/2 (0)
Non-naïve	3/6 (50)	0/1 (0)
Onset of ARDS in relation of duration of antibiotic treatment
Median number of days (range)	6 (2–15)	2 (2–5)
Developed ARDS 48-72 hours, n (%)
Naïve	2/3 (66)	2/2 (100)
Non-naïve	1/6 (17)	0/1 (0)
Death, n (%)	3/10 (30)	0/3 (0)

* Born and raised in TF nonendemic country.

† Surgery, presence of disseminated intravascular coagulation, and pneumonia.

Compounding the uncertainty of the pathophysiology of TF-associated ARDS is the lack of data for treatment. Some observational studies suggest that the combination of azithromycin with a third-generation cephalosporin may shorten the time until defervescence compared with monotherapy due to its improved intracellular activity against S. Typhi.^23,24 Moreover, adding azithromycin may be useful in ARDS because of its immunomodulatory and anti-inflammatory effects as has been shown in a recent study.²⁵ Yet, it is unclear whether such a therapeutic approach would help avoid the development or hasten the resolution of TF-associated ARDS. Of note, corticosteroids that have been recommended for patients with TF complicated by delirium, obtundation, stupor, coma, or shock may be a useful adjunct treatment in TF-associated ARDS as has been recently described in a case report.^5,26

In conclusion, ARDS and pARDS represent currently underappreciated serious complications of TF. As the patho-mechanism of TF-associated ARDS/pARDS are incompletely understood, and risk factors for developing ARDS/pARDS among patients with TF have not been defined, clinicians treating patients with presumed or confirmed TF need to add ARDS/pARDS as a potential complication of TF that may frequently occur within 48-72 hours of initiating effective antibiotic treatment.