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The Pediatric Infectious Disease Journal • Volume 29, Number 11, November 2010 3. Makhoul IR, Sujov P, Smolkin T, et al. Epidemiological, clinical, and microbiological characteristics of late-onset sepsis among very low birthweight infants in Israel: a national survey. Pediatrics. 2002;109:34 –39.
Therapies Used in 2008 (Before Prophylaxis) and 2009 4. Stoll BJ, Hansen N, Fanaroff AA, et al. Late-onset sepsis in very low birth (During Prophylaxis) for Premature Infants With Birth weight neonates: the experience of the NICHD Neonatal Research Net- work. Pediatrics. 2002;110:285–291.
5. Manzoni P, Farina D, Leonessa M, et al. Risk factors for progression to invasive fungal infection in preterm neonates with fungal colonization.
Pediatrics. 2006;118:2359 –2364.
6. Kaufman D, Boyle R, Hazen KC, et al. Fluconazole prophylaxis against fungal colonization and infection in preterm infants. N Engl J Med.
7. Benjamin DK Jr, DeLong ER, Steinbach WJ, et al. Empirical therapy for neonatal candidemia in very low birth weigh infants. Pediatrics. 2003;112:543–547.
8. Manzoni P, Stolfi H, Pungi L, et al. A multicenter, randomized trial of prophylactic fluconazol in preterm neonates. N Engl J Med. 2007;356: DISCUSSION
Many publications have determined that Candida species 9. Uko S, Soghier LM, Vega M, et al. Targeted short-term fluconazole constitute an important cause (9%–12%) of late-onset infections in prophylaxis among very low birth weight and extremely low birth weightinfants. Pediatrics. 2006;117:1243–1252.
VLBW infants in developed countries and are associated with 10. Bertini G, Perugi S, Dani C, et al. Fluconazole prophylaxis prevents case-fatality rates of 30% or greater in this birth weight group.1–7 invasive fungal infection in high-risk, very low birth weight infants.
Although several studies have demonstrated the efficacy of flu- J Pediatr. 2005;147:162–165.
conazole prophylaxis to reduce Candida infections in VLBW 11. Long SS, Stevenson DK. Reducing Candida infections during neonatal neonates, its use has not been widely accepted20,21 and scant intensive care: management choices, infection control, and fluconazole information is available from developing countries.
prophylaxis. J Pediatr. 2005;147:135–141.
In 2007, we noted that 10% of our NICU infants weighing 12. McGuire W, Clerihew L, Austin N. Prophylactic intravenous antifungal less than 1250 g developed fungal invasive infections, and roughly agents to prevent mortality and morbidity in very low birth weight infants.
Cochrane Database Syst Rev. 2004:CD003850.
half of them died.19 We implemented routine prophylaxis withfluconazole for this selected population, starting in January 2009 13. McCrossan B, McHenry E, OЈNeill F, et al. Selective fluconazol prophy- laxis in high-risk babies to reduce invasive fungal infection. Arch Dis Child and compared results with the figures of the precedent year.
Fetal Neonatal Ed. 2007;92:F454 –F458.
Similar to many other studies,8–18 we found a significant 14. Kaufman D, Boyle R, Hazen KC, et al. Twice weekly fluconazole prophy- reduction of invasive Candida infection in treated infants, from 7.7% laxis for prevention of invasive Candida infection in high-risk infants of in 2008 to 1.1% in 2009. We determined that 7 VLBW infants needed Ͻ1000 grams birth weight. J Pediatr. 2005;147:172–179.
to be treated to avoid one systemic fungal infection. Although the 15. Healy CM, Baker CJ, Zaccaria E, et al. Impact of fluconazole prophylaxis case-fatality rate of documented candidiasis was similar for both on rate and outcome of invasive candidiasis in a neonatal intensive care years, fewer infants died of Candida-associated infections. Without a unit. J Pediatr. 2005;147:166 –171.
thorough histopathologic examination of all deaths (very few autop- 16. Healy CM, Campbell JR, Zaccaria E, et al. Fluconazole prophylaxis in extremely low birth weight neonates reduces invasive candidiasis mortality sies were performed), with or without isolation of Candida in blood rates without emergence of fluconazole resistant Candida species. Pediat- cultures, it is impossible to conclude, however, that fluconazole prophylaxis decreased specific mortality. Important savings in admin- 17. Manzoni P, Ariso R, Mostert M, et al. Prophylactic fluconazole is effective istration of antifungal drugs were noted in our unit. Additionally, the in preventing fungal colonization and fungal systemic infections in preterm costs of diagnostic procedures and medical examinations evaluating neonates: a single-center, 6-year, retrospective cohort study. Pediatrics.
dissemination in the documented cases of invasive fungal infections would have resulted in even more hospital savings.
18. Aziz M, Patel AL, Losavio J, et al. Efficacy of fluconazole prophylaxis for prevention of invasive fungal infection in extremely low birth weight In conclusion, we believe that there is adequate information of infants. Pediatr Infect Dis J. 2010;29:352–356.
the benefits of fluconazole prophylaxis for VLBW infants managed in 19. Archivos Clínicos y de Laboratorio. Boletines Estadísticos del Hospital del units where Candida infections are commonly documented. Once this policy is started, a continuous evaluation of efficacy should be 20. Fanaroff AA. Fluconazole for the prevention of fungal infections: get ready, performed to anticipate future shifts in the species of Candida isolated get set, caution. Pediatrics. 2006;117:214 –215.
and in potential resistance to antifungal drugs.
21. Neely MN, Schreiber JR. Fluconazole prophylaxis in the very low birth weight infant: not ready for prime time. Pediatrics. 2001;107:404 – 405.
ACKNOWLEDGMENTS
The authors thank the laborious and rigorous work of all nurses, neonatologists, and housestaffs of our hospital. A special SEVERE COINFECTIONS OF DENGUE AND
recognition to Maribel Jaramillo, RN and Paul Gallardo, MD for PANDEMIC INFLUENZA A H1N1 VIRUSES
study support and prophylactic policy implementation. Maria Angeles Perez, MD,* Aubree Gordon, PhD,†‡ REFERENCES
Felix Sanchez, MD,* Federico Narvaez, MD,*§Gamaliel Gutierrez, MD,§ Oscar Ortega, MD,§ 1. Benjamin DK Jr, Stoll BJ, Fanaroff AA, et al. Neonatal candidiasis among extremely low birth weight infants: risk factors, mortality rates, Andrea Nun˜ez, MSc,¶ Eva Harris, PhD,† and neurodevelopmental outcomes at 18 to 22 months. Pediatrics.
Abstract: Here we report on 4 hospitalized patients with dengue-influenza
2. Cotten CM, McDonald S, Stoll B, et al. The association of third-generation cephalosporin use and invasive candidiasis in extremely low birth-weight virus coinfections. All patients were RT-PCR positive for dengue virus and infants. Pediatrics. 2006;118:717–722.
pandemic influenza A H1N1. Clinical findings at presentation ranged from 2010 Lippincott Williams & Wilkins The Pediatric Infectious Disease Journal • Volume 29, Number 11, November 2010 influenza-like illness to severe dengue. Clinical progression of the infections fever, characterized by abrupt-onset fever with headache, malaise, varied, but all developed dengue symptoms and had interstitial infiltrates.
retro-orbital pain, arthralgias, and/or myalgias, to severe dengue, Three cases required intensive care management and 1 case was fatal.
characterized by plasma leakage that may lead to shock and death.
Currently, there is no antiviral therapy for dengue; thus, treatment relies Key Words: dengue, influenza, coinfection, Nicaragua, children
on supportive care, primarily fluid and electrolyte management.4 Accepted for publication May 5, 2010.
Here we report on the clinical and epidemiological character- From the *Hospital Infantil Manuel de Jesu´s Rivera, Ministerio de Salud, Managua, Nicaragua; †Division of Infectious Diseases and Vaccinology, istics and laboratory findings from 4 patients with dengue virus University of California, Berkeley, CA; ‡Fogarty International Center, serotype 3 (DENV-3) and influenza A H1N1 coinfections. All pa- National Institutes of Health, Bethesda, MD; §Sustainable Sciences Insti- tients were hospitalized at the National Pediatric Reference Hospital, tute, Managua, Nicaragua; and ¶Departamento de Virología, Centro Nacio- Hospital Infantil Manuel Jesu´s Rivera (HIMJR), in Managua, Nica- nal de Diagno´stico y Referencia, Ministerio de Salud, Managua, Nicaragua.
Supported by the Pediatric Dengue Vaccine Initiative grant VE-1 (to E.H.), ragua. A summary of clinical characteristics is presented in Table 1.
NIH grant AI65359 (to E.H.), and the Fogarty International Center.
The authors declare that we do not have any conflict of interests.
CASE REPORTS
Address for Correspondence: Eva Harris, PhD, Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, 1 Barker Hall, Berkeley, CA 94720-7354. E-mail: A 5-year-old boy with a history of asthma and recent household exposure to H1N1 presented at a local health center in Boaco, Nicaragua, on September 2 with fever Ͼ40°C and pain onswallowing of 2 days duration, headache, arthralgias, myalgias, In April 2009, a new influenza A virus, pandemic H1N1, caused prostration, and loss of appetite. He was hospitalized 1 day later a severe outbreak in Mexico.1 The virus quickly spread throughout with a diagnosis of probable influenza in a local hospital and the world, and the World Health Organization declared a pandemic in treated with Oseltamivir (75 mg BID) for 2 days. The patient was June 2009.2 In Nicaragua, pandemic H1N1 was first detected on June transferred to HIMJR in critical condition 5 days postsymptom 1, and high levels of influenza transmission occurred from June to onset, and respiratory and blood samples were collected for RT- October. The influenza and dengue seasons in Nicaragua do not PCR, which subsequently revealed H1N1 and DENV-3 infection, normally overlap, with epidemics of influenza in May to July and respectively. Despite treatment, the patient’s condition deterio- dengue epidemics in August to December.3 High transmission of rated and he was reclassified as a suspected severe dengue case pandemic influenza outside the normal season resulted in an overlap because of decreasing platelet counts and increasing hematocrit, of influenza and dengue transmission in Nicaragua.
radiologic evidence of bilateral pleural effusions, and hepatomeg- Dengue virus infection can be asymptomatic or produce a aly, ascites, and enlarged gallbladder as evidenced by abdominal range of clinical presentations, from undifferentiated fever to dengue ultrasound. The patient developed shock and was transferred to the Clinical Characteristics of 4 Children With Dengue-influenza Virus Coinfections* *NP indicates not performed; AST, aspartate amino transferase; ALT, alanine amino transferase; IU, international units.
2010 Lippincott Williams & Wilkins The Pediatric Infectious Disease Journal • Volume 29, Number 11, November 2010 intensive care unit (ICU), where he was given IV saline solution dextran and dopamine were administered, and a central venous followed by dextran, albumin, and then norepinephrine. Mechan- catheter was inserted. BP improved and dopamine was reduced, ical ventilation was begun, and norepinephrine and oseltamivir but then somnolence and hypotension were noted, and endotra- (150 mg BID) were administered. A chest radiograph showed cheal intubation was performed. On the ninth day of illness, bilateral interstitial infiltrates. After 3 days in the ICU, the patient norepinephrine was substituted for dopamine, which stabilized continued to be febrile and present leukocytosis, a predominance BP. A second chest radiograph revealed increased bilateral of segmented neutrophils, and clinical evidence of severe acute infiltrates, and antibiotic therapy was changed to ceftriaxone.
respiratory distress, together with consistent radiographic changes.
Over the following 24 hours, the patient’s hemodynamic indices Antibiotic treatment was changed to imipenem and vancomycin.
and respiration status improved, which was reflected in a third Over the course of the following days, bronchospasms were treated chest radiograph. Norepinephrine was decreased, and the pa- with bronchodilators and corticosteroids. The patient improved tient was extubated after 65 hours of assisted ventilation in clinically and radiographically. He was extubated after 12 days of stable condition. She recovered fully and was discharged after mechanical ventilation, and vasopressure therapy was discontin- ued; he received a total of 14 days of double antibiotic therapy and18 days of oseltamivir. Following 21 days of hospitalization (14 days ICU), the patient was discharged in stable condition.
An 11-year-old girl with obesity and asthma presented at the emergency room of HIMJR on September 27 with a history of pain on swallowing for 1 day. The clinical examination was unremark- A 10-year-old girl presented at a primary care health center able and the patient was released with instructions to return if on September 3, the day of symptom onset, with a temperature of symptoms worsened. The following morning she presented with 39.5°C, headache, sore throat, arthralgias, and myalgias. She was the development of high fever, headache, arthralgias, and myalgias suspected of having influenza, and a respiratory sample was in the previous 12 hours. On examination, she was afebrile, collected. Additionally, a blood sample was collected for dengue breathing regularly, pale, had no hepatomegaly, and had pharyn- RT-PCR testing and complete blood count. The patient was in- geal hyperemia, tonsillar hypertrophy, abdominal tenderness, cold structed to return for follow-up visits for each of the following 4 extremities, poor capillary refill, and a weak pulse. She was days, during which time she complained of pain on swallowing transferred immediately to the critical care area with a presumptive and loss of appetite, and laboratory results confirmed a dengue diagnosis of severe dengue. Saline solution was administered infection. On the fifth day, she had a capillary refill Ն3 seconds, intravenously. Afterward, her pulse was 110 and BP was 130/50 was confirmed as a case of H1N1, given an IV of saline solution mm Hg; she continued to have cold extremities, capillary refill of (0.9%), and transferred to the HIMJR. She was admitted to HIMJR 4 seconds, and a weak pulse. Two additional boluses of saline in hemodynamically stable condition with a positive tourniquet solution and then dextran were administered, but the patient test, skin rash, and crepitations at both lung bases. Treatment was continued to have low diastolic BP (110/55). She was treated with initiated with oral fluids, acetaminophen, oseltamivir (75 mg BID), dopamine, oxygen, and IV saline solution. Chest radiograph and continual monitoring of hemodynamic state. The following revealed bilateral interstitial and alveolar infiltrates. A diagno-sis of pneumonia was made and cefotaxime treatment initiated.
day, a complete blood count revealed thrombocytopenia and leu- Ultrasound revealed a distended gallbladder with thin walls kocytopenia, and a chest radiograph showed bilateral interstitial (2 mm), and an echocardiogram was normal. The patient con- infiltrates. The patient continued in a stable state and was dis- tinued in unstable condition with low diastolic pressure, so charged after 4 days of hospitalization.
sepsis was suspected. Norepinephrine was substituted for do- pamine. The patient was intubated and the dosing of norepi-nephrine was increased. Abundant blood-tinged mucous was A 5-year-old girl with a history of asthma presented with removed through the endotracheal tube. Eleven hours after a temperature of 39.2°C, sore throat, cough, runny nose, swol- presenting at the hospital, the patient developed cardiac arrest len cervical lymph nodes, vomiting, and a positive tourniquet and efforts to resuscitate her were unsuccessful. The cause of test, on September 15, 2 days postonset of illness. Specimens death was recorded as dengue shock syndrome. A respiratory were collected for influenza and dengue testing. The family was sample collected immediately post mortem and a blood sample provided oseltamivir; however, the parents chose not to admin- collected at admission were positive for influenza A H1N1 and ister it to the child. The patient returned the following day with continuing symptoms and loss of appetite, retro-orbital pain,headache, myalgias, arthralgias, and back pain. On the fifth daypostonset, she was given IV saline solution and transferred to HIMJR. Upon admission, the patient was well-hydrated with A blood sample and nasal and throat swabs were collected the following signs, symptoms, and findings on physical exam- for dengue and influenza testing, respectively. Cases were tested ination: malaise, somnolence, hepatomegaly, cold extremities, for DENV-1– 4 by RT-PCR targeting the capsid gene.5 The Cen- diaphoresis, capillary refill Ͼ3 seconds, and a weak pulse. She ters for Disease Control and Prevention’s qRT-PCR protocol was was given IV saline solution and admitted to the ICU. Chest followed for the detection of pandemic influenza A H1N1.6 Lab- radiograph revealed bilateral interstitial infiltrates. Laboratory oratory tests were performed at the Nicaraguan National Virology results confirmed H1N1 infection, and oseltamivir treatment (120 mg BID) was started. Ampicillin was initiated for a Comment. We present 4 documented DENV-influenza A H1N1 coinfections in children; all 4 were RT-PCR positive for both The patient continued in stable condition, and was con- viruses. In 3 cases, samples for influenza and dengue RT-PCR firmed to have DENV-3 infection by RT-PCR. On the eighth testing were taken on the same day; in case 4, the influenza sample day of illness, she developed hypotension, which initially re- was taken postmortem, 1 day after the sample for dengue. While sponded to administration of saline solution; however, 6 hours bilateral interstitial and/or alveolar infiltrates were present in all 4 later, her diastolic blood pressure (BP) decreased rapidly; cases, the clinical presentation of the 4 cases varied and a single 2010 Lippincott Williams & Wilkins The Pediatric Infectious Disease Journal • Volume 29, Number 11, November 2010 Congenital Histoplasmosis in an Infant pattern was not observed. Three patients had a history of asthma,a known risk factor both for severe dengue and influenza.7–10 A HUMAN IMMUNODEFICIENCY VIRUS-POSITIVE
In case 1, respiratory symptoms were absent. Due to asthma INFANT WITH PROBABLE CONGENITAL
and close contact with a confirmed H1N1 case, the patient was HISTOPLASMOSIS IN A NONENDEMIC AREA
given oseltamivir very early, which may have prevented respira- Brian Alverson, MD,* Nicole Alexander, MD,† tory symptoms and resulted in a predominately dengue-like clin- Mark P. LeGolvan, DO,‡ Whitney Dunlap, MD,§ ical presentation, which evolved into shock, possibly aggravatedby a bacterial infection. In contrast, case 2 presented with classic flu-like symptoms, including cough, as well as classic dengue Abstract: A 5-week-old infant presented with a fever, and was diagnosed
symptoms. This patient, though hospitalized, had an illness of only with congenital human immunodeficiency virus and histoplasmosis. Both mild-to-moderate severity, possibly due to early treatment with IV infections were likely transmitted vertically. The child was effectively fluids when the patient began to display signs of hemodynamic treated with antifungal medications and highly active antiretroviral therapy.
instability. This patient is the only 1 of the 4 cases with no prior This represents the first case of delayed presentation of vertically trans- history of underlying conditions predisposing to severe influenza mitted histoplasmosis, and the first case in a nonendemic area.
and dengue. In the third case, respiratory symptoms preceded thedevelopment of dengue symptoms. Oseltamivir treatment was not Key Words: HIV, histoplasmosis, disseminated histoplasmosis, infant
started until after the child was hospitalized and developing he- Accepted for publication May 6, 2010.
From the *Department of Pediatrics, Hasbro Children’s Hospital, Brown Uni- modynamic instability. Shock in this patient was different from versity, Providence, RI; †Department of Infectious Diseases, Brown Uni- case 1 and was atypical for dengue, in which the observed versity, Providence, RI; ‡Surgical Pathology Department, Brown Univer- hypotension is usually limited to the systolic component. Initially, sity, Providence, RI; §Department of Allergy and Immunology, University the patient was diagnosed with viral pneumonia, followed by of Michigan, Ann Arbor, MI; and ¶Department of Pediatrics, ThomasJefferson University, Philadelphia, PA.
bacterial pneumonia. The fourth case presented with classic den- The authors note that there were no potential, perceived, or real conflict of gue symptoms and rapidly went into shock. Onset of shock 2 days interest, or financial arrangements (eg, grants received, advisory board rather than 4 to 6 days postsymptom onset is unusual for dengue, memberships, share holdings) with any company in the preparation of as is a markedly reduced diastolic BP (as in case 3).
this manuscript. There were no sponsors, financially or otherwise, of In conclusion, we present 4 children with laboratory-con- any of the work that went into the creation of this manuscript.
firmed dengue-influenza virus coinfections with varying clinical Address for correspondence: Brian Alverson, MD, Department of Pediatrics, presentations, and based on this experience, find that coinfections Hasbro Children’s Hospital, Brown University, Potter Building, Room may be a risk factor for severe disease. Due to the range of clinical 108, 593 Eddy Street, Providence, RI. E-mail: balverson@lifespan.org.
presentation and difficulties differentiating DENV-influenza coinfec- Supplemental digital content is available for this article. Direct URL tions from single infections, especially early on, it is advisable that citations appear in the printed text and are provided in the HTML and testing for both viruses be performed when they are cocirculating.
PDF versions of this article on the journal’s Web site (www.pidj.com).
ACKNOWLEDGMENTS
The authors thank the staff at the Hospital Infantil Manuel de Jesu´s Rivera and at the health center So´crates Flores Vivas for Histoplasmosis is common in many parts of the world. A majority of cases are mild and self-limited; however, infants their invaluable assistance and Arthur Reingold for editorial often present with disseminated disease. Disseminated histoplas- comments. The authors also thank the patients and their families. mosis in infants carries a mortality between 83% and 93%,rendering rapid definitive diagnosis critical.1 Where the spores are REFERENCES
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a nurse in the emergency room incurred a needle-stick, and Western blot human immunodeficiency virus (HIV) test was per- 2010 Lippincott Williams & Wilkins

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