Necrotizing Fasciitis Caused by Haemophilus influenzae Serotype f
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Christopher J. Arnold, Grant Garrigues, Joseph W. St. Geme III and Daniel J. Sexton J. Clin. Microbiol. 2014, 52(9):3471. DOI: 10.1128/JCM.01460-14. Published Ahead of Print 2 July 2014.
CASE REPORT
Necrotizing Fasciitis Caused by Haemophilus influenzae Serotype f Christopher J. Arnold,a Grant Garrigues,b Joseph W. St. Geme III,c Daniel J. Sextona Division of Infectious Disease, Duke University Medical Center, Durham, North Carolina, USAa; Division of Orthopedic Surgery, Duke University Medical Center, Durham, North Carolina, USAb; Department of Pediatrics, Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USAc
CASE REPORT
A
63-year-old female came to the Duke University Medical Center Emergency Department in February 2013 because of a fever and increasing right hip and right shoulder pain that had occurred over a 5-day period. Her medical history was notable for stage II breast cancer treated with a left mastectomy and six cycles of cyclophosphamide and adriamycin in 1996 and for hypothyroidism, mitral valve prolapse, and hyperlipidemia. Several days prior to hospitalization, the patient had cared for a grandchild with a mild upper respiratory illness. Two days later, the patient noted mild throat discomfort. The following day, she went on a 4-mile run and then did yoga and weight training. Later that day, chills occurred. Her temperature rose to 104°F, and she took ibuprofen. The next morning, she noted pains in her right groin and right shoulder and sought evaluation at a local emergency department. Results of basic laboratory testing and a nasal swab for influenza virus were normal or negative; thus, she was discharged without a specific diagnosis and with instructions to take analgesics and rest. The following day, her right shoulder and groin pain were worse. She was seen in the office of an orthopedic surgeon, who prescribed methyl prednisolone. Her pain intensified over the next 2 days, and thus, she went to the Emergency Department at Duke University Medical Center, where an examination showed a normal temperature and blood pressure. Passive and active movements of her right shoulder and right hip were limited by pain. The soft tissues overlying the right shoulder from the deltoid to the midhumerus and from the region of the pubic symphysis to the right medial thigh were indurated and erythematous. Initial laboratory tests showed the following: C-reactive protein (CRP) level, 37.6 mg/dl; erythrocyte sedimentation rate (ESR), 91 mm/h; creatinine level, 2.7 mg/dl; platelet count, 110 ⫻ 109 cells/liter; white blood cell count, 2.4 ⫻ 109 cells/liter (36% bands); aspartate transaminase (AST) level, 48 U/liter; and creatinine kinase level, 195 U/liter (30 to 220 U/liter). Blood and urine specimens were obtained for cultures, and treatment with vancomycin and ceftriaxone was initiated. Following admission, ceftriaxone was discontinued, and treatment with clindamycin and cefepime was begun. A consulting orthopedic surgeon attempted to aspirate the right shoulder, but no joint fluid could be detected. Aspiration of the right hip recovered a small amount of fluid containing 83 white blood cells/l (44% polymorphonuclear cells); no organisms were seen on the Gram stain. A subsequent magnetic resonance imaging study revealed findings consistent with nonspecific myositis and fasciitis
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involving the right shoulder and arm and right hip and thigh, a small right hip effusion, and a large right glenohumeral effusion with changes suggesting synovitis. Sixteen hours after admission, blood cultures revealed growth of small Gram-negative rods. A consultant from the Infectious Disease Service recommended addition of doxycycline to cover for the possibility of Vibrio, given recent shellfish consumption. Within hours of the receipt of a report of positive blood cultures, the patient developed tachypnea and tachycardia. These findings in turn led to surgical debridement. The skin overlying the antecubital fossa was dusky, and there was a “spider web” appearance to the underlying subcutaneous and deeper tissue due to thrombosed veins. Cloudy fluid was observed tracking along facial planes, interspersed with areas of thickened fibrotic fascia. Debridement was extensive, including large amounts of fibrotic rind overlying the fascia as well as a small amount of bicep muscle. The long head of the bicep tendon sheath was also found to be swollen with purulent fluid. The glenohumeral joint was also accessed and irrigated. Simultaneous to the upper limb surgery, a second operative team incised infected tissue extending from the medial aspect of the knee to an area just distal to the labia majora in the inguinal crease. Given the gross appearance of necrotizing faciitis, emergent, simultaneous shoulder and hip disarticulation were considered, but an initial strategy of limb-sparing, but aggressive, debridement was chosen. Close surgical follow-up was maintained in case amputation became necessary. Septic shock necessitating multiple vasopressors for blood pressure support occurred in the early postoperative period. A Gram stain of purulent fluid from the operative debridement revealed small Gram-negative rods similar to those seen in the blood cultures. On hospital day 3, the organism isolated from her blood cultures was identified as Haemophilus influenzae, not type b, beta-lactamase negative; ultimately, the organism was determined to be serotype f, biotype I. With this information, she was initiated
Received 21 May 2014 Returned for modification 16 June 2014 Accepted 24 June 2014 Published ahead of print 2 July 2014 Editor: A. J. McAdam Address correspondence to Christopher J. Arnold, [email protected]. Copyright © 2014, American Society for Microbiology. All Rights Reserved. doi:10.1128/JCM.01460-14
Journal of Clinical Microbiology
p. 3471–3474
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Haemophilus influenzae is a rare cause of soft tissue infection. In this report, we present a case of multifocal necrotizing fasciitis in a healthy adult patient, secondary to Haemophilus influenzae serotype f infection, and we review literature on this rare cause of necrotizing fasciitis.
Case Report
TABLE 1 Summary of cases of Haemophilus influenzae necrotizing fasciitis reported in the literature to date Source or reference
Patient age
Comorbidity(ies)a
Serotype
Location(s) of disease
Surgical treatment
6
19 mo
None
Nasopharynx, pharynx, and palate
Debridement of nasopharynx, pharynx, and palate
Yes
13
45 yr
DM1, MGUS
Nontypeable (polymicrobial infection) Nontypeable
Limb-sparing debridements
Yes
11
17 yr
SLE
e
Limb-sparing debridement of all 4 extremities
No
8 9
13 mo 44 yr
None None
b b
Limb-sparing debridements Limb-sparing debridements
Yes Yes
7
64 yr
None
b
Debridement of chest wall
Yes
12 10 5
81 yr 65 yr 70 yr
DM2 Alcohol abuse None (later found to have IgG3 and mannose-binding lectin deficiency)
b f f
Gluteal region and lower extremity Began as upper extremity; progressed to involve all extremities, thorax, abdomen, and pelvis Lower extremity Gluteal region (site of paracetamol injections) Chest wall (associated with concomitant epiglottitis) Lower extremity Lower extremity Both lower and upper extremities
Yes No Yes
2 Present study
86 yr 63 yr
Parkinson’s disease Remote history of breast cancer
f f
Limb-sparing debridements Above-the-knee amputation Debridement of extremities and subsequent amputation of toes bilaterally Limb-sparing debridements Limb-sparing debridements
Yes Yes
DM1, diabetes mellitus type 1; DM2, diabetes mellitus type 2; MGUS, monoclonal gammopathy of undetermined significance; SLE, systemic lupus erythematosus.
on ceftriaxone at 2 g intravenously (i.v.) every 24 h (q24h), and all other antibiotics were discontinued. Multiple repeat trips to the operating room (OR) for repeated debridements occurred over the next several days. Ultimately, seven debridements and six sessions of hyperbaric oxygen therapy were used to control her necrotizing infection. A transthoracic echocardiogram revealed no valvular vegetations, and her blood cultures cleared rapidly, with negative surveillance cultures done on hospital day 3. She was extubated on hospital day 7, and treatment with vasopressors was stopped on hospital day 8. Her subsequent hospital course was complicated by the development of Clostridium difficile colitis. She was discharged on hospital day 24 and completed a 36-day course of ceftriaxone. She was seen in follow-up in the Infectious Disease Clinic at the completion of her antibiotic therapy and was well. Six months later, she was completely well. She continues to stay physically active, notably with running and yoga, and notes no deficits.
Haemophilus influenzae is a small Gram-negative coccobacillus most commonly found in the human respiratory tract (1). Historically, H. influenzae serotype b (Hib) is the most common and virulent type. However, with the advent of Hib vaccination, there has been a dramatic decrease in the incidence of infections due to Hib (2). Concomitant with this decrease, there has been an increase in the recognition of serious infections with non-b-type and nontypeable H. influenzae isolates (2–5). The most common forms of disease associated with H. influenzae are infections of the respiratory tract such as pneumonia and exacerbations of chronic obstructive pulmonary disease (COPD). While H. influenzae has been associated with cellulitis, this occurs mostly in children in the head and neck region; reports
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of H. influenzae causing other soft tissue infection are extremely rare (1). H. influenzae serotype f (Hif), in particular, is an increasingly important cause of invasive disease (3). There are two recent reviews of Hif disease in the literature. First, in 1996, Urwin et al. (3) reviewed 91 cases of invasive Hif infection. Seventy-two percent of these cases occurred in adults, with an overall mortality rate of 30%. A large majority of the patients (78%) had significant underlying comorbidity, most commonly COPD, alcohol abuse, diabetes, or malignancy. Eighty-two percent of cases were infections of the respiratory tract, and there were no reported cases of necrotizing soft tissue infection. More recently, Bruun et al. (4) published a review of 13 cases of invasive Hif disease. Again, respiratory disease was most common (8/13 cases). The other diseases included one each of the following: meningitis, epiglottitis, osteomyelitis, cholangitis, and neutropenic bacteremia without identifiable focus. Again, there were no reported cases of soft tissue infection. In our review, there are only 10 cases of necrotizing fasciitis associated with H. influenzae reported in the literature, 7 of which occurred in adults (Table 1) (2, 5–13). Three cases were secondary to Hif infection, as occurred for our patient. In one of the three reported cases of Hif necrotizing fasciitis, the disease was multifocal in noncontiguous sites, affecting both the upper and the lower extremities (5). This is a distribution of disease similar to that for our patient, with both upper and lower extremities affected. Like our patient, all three patients in the cases reviewed developed signs of severe sepsis and shock complicated by significant thrombocytopenia as well as leukopenia, which can often be seen in severe sepsis caused by Gram-negative bacteria. This information is consistent with the severe systemic illness often manifesting as a complication of necrotizing fasciitis.
Journal of Clinical Microbiology
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a
Lower extremity Both lower and upper extremities
Survival to discharge
Case Report
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very rare, has been reported in the literature and may be an underappreciated disease. When caring for a patient with suspected necrotizing fasciitis, a Gram stain suggestive of this possibility should prompt empirical antimicrobial coverage. It is important to remember that due to this organism’s pleomorphism, Gram stains can often be misinterpreted. Thus, we would suggest that in patients for whom a Gram stain is interpreted as small Gramnegative organisms of any morphology (be it rods, bacilli, or coccobacilli), this diagnosis be considered and antimicrobial therapy that empirically covers this possibility be initiated. While most cases of infection appear to occur in patients less than 2 years or greater than 60 years of age, the infection has been seen in younger individuals. Also, while comorbidities such as diabetes, malignancy, and alcohol abuse may be seen, the infection can also occur in individuals thought to be previously healthy. As is the case with other causes of necrotizing fasciitis, therapy should consist of a combination of antimicrobial therapy and aggressive surgical debridement. REFERENCES 1. Murphy TF. 2009. Haemophilus species (including H. influenzae and chancroid), p 2911–2919. In Mandell GL, Bennett JE, Dolin R (ed), Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, vol 2, 7th ed. Churchill Livingstone, Philadelphia, PA. 2. Hagiya H, Murase T, Naito H, Hagioka S, Morimoto N. 2012. Severe soft tissue infection of the lower extremity caused by Haemophilus influenzae (serotype f, biotype II) in an adult patient. Intern. Med. 51:1783– 1787. http://dx.doi.org/10.2169/internalmedicine.51.7209. 3. Urwin G, Krohn JA, Deaver-Robinson K, Wenger JD, Farley MM. 1996. Invasive disease due to Haemophilus influenzae serotype f: clinical and epidemiologic characteristics in the H. influenzae serotype b vaccine era. The Haemophilus influenzae Study Group. Clin. Infect. Dis. 22:1069 –1076. 4. Bruun B, Gahrn-Hansen B, Westh H, Kilian M. 2004. Clonal relationship of recent invasive Haemophilus influenzae serotype f isolates from Denmark and the United States. J. Med. Microbiol. 53:1161–1165. http: //dx.doi.org/10.1099/jmm.0.45749-0. 5. Resman F, Svensjo T, Unal C, Cronqvist J, Brorson H, Odenholt I, Riesbeck K. 2011. Necrotizing myositis and septic shock caused by Haemophilus influenzae type f in a previously healthy man diagnosed with an IgG3 and a mannose-binding lectin deficiency. Scand. J. Infect. Dis. 43:972–976. http://dx.doi.org/10.3109/00365548.2011.589079. 6. Bush JK, Givner LB, Whitaker SH, Anderson DC, Percy AK. 1984. Necrotizing fasciitis of the parapharyngeal space with carotid artery occlusion and acute hemiplegia. Pediatrics 73:343–347. 7. Chalmers C. 2010. Necrotising fasciitis complicating Haemophilus influenzae type b epiglottitis in an adult. J. Laryngol. Otol. 124:807– 809. http: //dx.doi.org/10.1017/S0022215109992076. 8. Collette CJ, Southerland D, Corrall CJ. 1987. Necrotizing fasciitis associated with Haemophilus influenzae type b. Am. J. Dis. Child. 141:1146 – 1148. 9. Lee EY, Ip WY. 2010. Necrotizing fasciitis of the extremity caused by Haemophilus influenzae serotype b in a healthy adult. Clin. Orthop. Relat. Res. 468:1436 –1439. http://dx.doi.org/10.1007/s11999-009-1126-x. 10. McLellan E, Suvarna K, Townsend R. 2008. Fatal necrotizing fasciitis caused by Haemophilus influenzae serotype f. J. Med. Microbiol. 57:249 – 251. http://dx.doi.org/10.1099/jmm.0.47603-0. 11. Robinson AB, DeWitt EM, Schanberg LE, Moody MA. 2010. Necrotizing fasciitis caused by Haemophilus influenzae type E in a 17-year-old girl with systemic lupus erythematosus. J. Clin. Rheumatol. 16:49 –50. http: //dx.doi.org/10.1097/RHU.0b013e3181c7e095. 12. Saito T, Matsunaga H, Matsumura Y, Segawa H, Takakura S, Nagao M, Iinuma Y, Miyachi Y, Ichiyama S. 2009. Necrotizing fasciitis caused by Haemophilus influenzae type b in an elderly patient. J. Clin. Microbiol. 47:852– 854. http://dx.doi.org/10.1128/JCM.01196-08. 13. Stumvoll M, Fritsche A. 1997. Necrotizing fasciitis caused by unencapsulated Haemophilus influenzae. Clin. Infect. Dis. 25:327. http://dx.doi .org/10.1086/516908. 14. St. Geme JW III, Cutter D, Barenkamp SJ. 1996. Characterization of the
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It is not clear what factors are responsible for predisposition to this rare infection. In our case, one would presume that the infection was likely acquired from the patient’s grandchild. However, how and why the infection then spread to the deep tissues of the extremities is unclear. There is likely a combination of host-specific and/or pathogen-specific factors that create an opportunity for this disease to manifest; however, the nature of these factors remains unclear. In the review of invasive Hif disease by Urwin et al. (3), there was an apparent predilection for hosts with significant underlying comorbidity, 78% of patients having at least one significant medical comorbidity. However, despite a remote history of breast cancer, our patient was otherwise healthy and in excellent physical condition at the time of presentation. Also, in the review of the prior reported cases, at least four were found to have occurred in relatively healthy individuals (5, 7, 9, 12). In one case of a previously healthy man, an IgG3 and mannose-lectin binding deficiency was later discovered, which was thought to have possibly been a predisposing factor (5). However, immune testing of this type is not common practice, and no other reported cases investigated this possibility. According to the review of the literature, this infection does seem to be most common at the extremes of age, with all but three cases occurring in individuals under the age of 2 or over the age of 60. There may be some age-related factors that play a role in the disease, but again, what these may be is not currently clear. In this case, further testing in the laboratory of an expert on Haemophilus disease was done. The isolate was found to be biotype I. Southern analysis showed it to contain the Hsf adhesin gene and the Hap adhesin/invasin gene, both of which are universally present in encapsulated isolates of H. influenzae (14–16). Additionally, no increased cytotoxicity was detected, based on light microscopy and lactate dehydrogenase (LDH) release using in vitro assays with Chang epithelial cells with a prototype H. influenzae type b strain (Eagan) and a prototype nontypeable H. influenzae strain (strain 12) (17). In summary, no unusual factors for increased virulence were detected by this extensive supplementary testing. The mainstay of treatment for necrotizing fasciitis is early surgical intervention. All cases reviewed in the literature were treated with a combined medical and surgical approach. While we certainly advocate life-saving treatment over limb-saving treatment, in our case, we were able to aggressively debride the upper and lower limbs while preserving function by isolating the neurovascular structures from the infectious material initially, allowing extensive removal of skin, subcutaneous tissue, fascia, muscle, and fibrotic material without sacrificing function. In this patient, ipsilateral forequarter and hindquarter amputations were not necessary, but in other cases they may be. Continued postoperative surveillance for residual infection is required, as further returns to the OR may be required even within hours of return from surgery. As with many rare diseases, it is likely that this infection occurs more frequently than what is reported in the literature. Indeed, the relatively high overall survival rate in the reported cases (which would be contrary to the expected overall survival rate in necrotizing fasciitis) would underscore the propensity of reporting bias, with cases with successful outcomes often chosen for publication. As such, it is possible that necrotizing fasciitis due to Haemophilus influenzae, while still a rare entity, does indeed occur more frequently than originally thought. In conclusion, this case highlights several notable and important points. Haemophilus influenzae necrotizing fasciitis, while
Case Report
genetic locus encoding Haemophilus influenzae type b surface fibrils. J. Bacteriol. 178:6281– 6287. 15. O’Neill JM, St. Geme JW III, Cutter D, Adderson EE, Anyanwu J, Jacobs RF, Schutze GE. 2003. Invasive disease due to nontypeable Haemophilus influenzae among children in Arkansas. J. Clin. Microbiol. 41: 3064 –3069. http://dx.doi.org/10.1128/JCM.41.7.3064-3069.2003. 16. Omikunle A, Takahashi S, Ogilvie CL, Wang Y, Rodriguez CA, St.
Geme JW III, Adderson EE. 2002. Limited genetic diversity of recent invasive isolates of non-serotype b encapsulated Haemophilus influenzae. J. Clin. Microbiol. 40:1264 –1270. http://dx.doi.org/10.1128/JCM.40.4 .1264-1270.2002. 17. Kehl-Fie TE, St. Geme JW III. 2007. Identification and characterization of an RTX toxin in the emerging pathogen Kingella kingae. J. Bacteriol. 189:430 – 436. http://dx.doi.org/10.1128/JB.01319-06.
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Journal of Clinical Microbiology
Updated information and services can be found at: http://jcm.asm.org/content/52/9/3471 These include: REFERENCES
CONTENT ALERTS
This article cites 17 articles, 10 of which can be accessed free at: http://jcm.asm.org/content/52/9/3471#ref-list-1 Receive: RSS Feeds, eTOCs, free email alerts (when new articles cite this article), more»
Information about commercial reprint orders: http://journals.asm.org/site/misc/reprints.xhtml To subscribe to to another ASM Journal go to: http://journals.asm.org/site/subscriptions/
Downloaded from http://jcm.asm.org/ on September 16, 2014 by Universitaetsbibliothek Bern
Christopher J. Arnold, Grant Garrigues, Joseph W. St. Geme III and Daniel J. Sexton J. Clin. Microbiol. 2014, 52(9):3471. DOI: 10.1128/JCM.01460-14. Published Ahead of Print 2 July 2014.
CASE REPORT
Necrotizing Fasciitis Caused by Haemophilus influenzae Serotype f Christopher J. Arnold,a Grant Garrigues,b Joseph W. St. Geme III,c Daniel J. Sextona Division of Infectious Disease, Duke University Medical Center, Durham, North Carolina, USAa; Division of Orthopedic Surgery, Duke University Medical Center, Durham, North Carolina, USAb; Department of Pediatrics, Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USAc
CASE REPORT
A
63-year-old female came to the Duke University Medical Center Emergency Department in February 2013 because of a fever and increasing right hip and right shoulder pain that had occurred over a 5-day period. Her medical history was notable for stage II breast cancer treated with a left mastectomy and six cycles of cyclophosphamide and adriamycin in 1996 and for hypothyroidism, mitral valve prolapse, and hyperlipidemia. Several days prior to hospitalization, the patient had cared for a grandchild with a mild upper respiratory illness. Two days later, the patient noted mild throat discomfort. The following day, she went on a 4-mile run and then did yoga and weight training. Later that day, chills occurred. Her temperature rose to 104°F, and she took ibuprofen. The next morning, she noted pains in her right groin and right shoulder and sought evaluation at a local emergency department. Results of basic laboratory testing and a nasal swab for influenza virus were normal or negative; thus, she was discharged without a specific diagnosis and with instructions to take analgesics and rest. The following day, her right shoulder and groin pain were worse. She was seen in the office of an orthopedic surgeon, who prescribed methyl prednisolone. Her pain intensified over the next 2 days, and thus, she went to the Emergency Department at Duke University Medical Center, where an examination showed a normal temperature and blood pressure. Passive and active movements of her right shoulder and right hip were limited by pain. The soft tissues overlying the right shoulder from the deltoid to the midhumerus and from the region of the pubic symphysis to the right medial thigh were indurated and erythematous. Initial laboratory tests showed the following: C-reactive protein (CRP) level, 37.6 mg/dl; erythrocyte sedimentation rate (ESR), 91 mm/h; creatinine level, 2.7 mg/dl; platelet count, 110 ⫻ 109 cells/liter; white blood cell count, 2.4 ⫻ 109 cells/liter (36% bands); aspartate transaminase (AST) level, 48 U/liter; and creatinine kinase level, 195 U/liter (30 to 220 U/liter). Blood and urine specimens were obtained for cultures, and treatment with vancomycin and ceftriaxone was initiated. Following admission, ceftriaxone was discontinued, and treatment with clindamycin and cefepime was begun. A consulting orthopedic surgeon attempted to aspirate the right shoulder, but no joint fluid could be detected. Aspiration of the right hip recovered a small amount of fluid containing 83 white blood cells/l (44% polymorphonuclear cells); no organisms were seen on the Gram stain. A subsequent magnetic resonance imaging study revealed findings consistent with nonspecific myositis and fasciitis
September 2014 Volume 52 Number 9
involving the right shoulder and arm and right hip and thigh, a small right hip effusion, and a large right glenohumeral effusion with changes suggesting synovitis. Sixteen hours after admission, blood cultures revealed growth of small Gram-negative rods. A consultant from the Infectious Disease Service recommended addition of doxycycline to cover for the possibility of Vibrio, given recent shellfish consumption. Within hours of the receipt of a report of positive blood cultures, the patient developed tachypnea and tachycardia. These findings in turn led to surgical debridement. The skin overlying the antecubital fossa was dusky, and there was a “spider web” appearance to the underlying subcutaneous and deeper tissue due to thrombosed veins. Cloudy fluid was observed tracking along facial planes, interspersed with areas of thickened fibrotic fascia. Debridement was extensive, including large amounts of fibrotic rind overlying the fascia as well as a small amount of bicep muscle. The long head of the bicep tendon sheath was also found to be swollen with purulent fluid. The glenohumeral joint was also accessed and irrigated. Simultaneous to the upper limb surgery, a second operative team incised infected tissue extending from the medial aspect of the knee to an area just distal to the labia majora in the inguinal crease. Given the gross appearance of necrotizing faciitis, emergent, simultaneous shoulder and hip disarticulation were considered, but an initial strategy of limb-sparing, but aggressive, debridement was chosen. Close surgical follow-up was maintained in case amputation became necessary. Septic shock necessitating multiple vasopressors for blood pressure support occurred in the early postoperative period. A Gram stain of purulent fluid from the operative debridement revealed small Gram-negative rods similar to those seen in the blood cultures. On hospital day 3, the organism isolated from her blood cultures was identified as Haemophilus influenzae, not type b, beta-lactamase negative; ultimately, the organism was determined to be serotype f, biotype I. With this information, she was initiated
Received 21 May 2014 Returned for modification 16 June 2014 Accepted 24 June 2014 Published ahead of print 2 July 2014 Editor: A. J. McAdam Address correspondence to Christopher J. Arnold, [email protected]. Copyright © 2014, American Society for Microbiology. All Rights Reserved. doi:10.1128/JCM.01460-14
Journal of Clinical Microbiology
p. 3471–3474
jcm.asm.org
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Downloaded from http://jcm.asm.org/ on September 16, 2014 by Universitaetsbibliothek Bern
Haemophilus influenzae is a rare cause of soft tissue infection. In this report, we present a case of multifocal necrotizing fasciitis in a healthy adult patient, secondary to Haemophilus influenzae serotype f infection, and we review literature on this rare cause of necrotizing fasciitis.
Case Report
TABLE 1 Summary of cases of Haemophilus influenzae necrotizing fasciitis reported in the literature to date Source or reference
Patient age
Comorbidity(ies)a
Serotype
Location(s) of disease
Surgical treatment
6
19 mo
None
Nasopharynx, pharynx, and palate
Debridement of nasopharynx, pharynx, and palate
Yes
13
45 yr
DM1, MGUS
Nontypeable (polymicrobial infection) Nontypeable
Limb-sparing debridements
Yes
11
17 yr
SLE
e
Limb-sparing debridement of all 4 extremities
No
8 9
13 mo 44 yr
None None
b b
Limb-sparing debridements Limb-sparing debridements
Yes Yes
7
64 yr
None
b
Debridement of chest wall
Yes
12 10 5
81 yr 65 yr 70 yr
DM2 Alcohol abuse None (later found to have IgG3 and mannose-binding lectin deficiency)
b f f
Gluteal region and lower extremity Began as upper extremity; progressed to involve all extremities, thorax, abdomen, and pelvis Lower extremity Gluteal region (site of paracetamol injections) Chest wall (associated with concomitant epiglottitis) Lower extremity Lower extremity Both lower and upper extremities
Yes No Yes
2 Present study
86 yr 63 yr
Parkinson’s disease Remote history of breast cancer
f f
Limb-sparing debridements Above-the-knee amputation Debridement of extremities and subsequent amputation of toes bilaterally Limb-sparing debridements Limb-sparing debridements
Yes Yes
DM1, diabetes mellitus type 1; DM2, diabetes mellitus type 2; MGUS, monoclonal gammopathy of undetermined significance; SLE, systemic lupus erythematosus.
on ceftriaxone at 2 g intravenously (i.v.) every 24 h (q24h), and all other antibiotics were discontinued. Multiple repeat trips to the operating room (OR) for repeated debridements occurred over the next several days. Ultimately, seven debridements and six sessions of hyperbaric oxygen therapy were used to control her necrotizing infection. A transthoracic echocardiogram revealed no valvular vegetations, and her blood cultures cleared rapidly, with negative surveillance cultures done on hospital day 3. She was extubated on hospital day 7, and treatment with vasopressors was stopped on hospital day 8. Her subsequent hospital course was complicated by the development of Clostridium difficile colitis. She was discharged on hospital day 24 and completed a 36-day course of ceftriaxone. She was seen in follow-up in the Infectious Disease Clinic at the completion of her antibiotic therapy and was well. Six months later, she was completely well. She continues to stay physically active, notably with running and yoga, and notes no deficits.
Haemophilus influenzae is a small Gram-negative coccobacillus most commonly found in the human respiratory tract (1). Historically, H. influenzae serotype b (Hib) is the most common and virulent type. However, with the advent of Hib vaccination, there has been a dramatic decrease in the incidence of infections due to Hib (2). Concomitant with this decrease, there has been an increase in the recognition of serious infections with non-b-type and nontypeable H. influenzae isolates (2–5). The most common forms of disease associated with H. influenzae are infections of the respiratory tract such as pneumonia and exacerbations of chronic obstructive pulmonary disease (COPD). While H. influenzae has been associated with cellulitis, this occurs mostly in children in the head and neck region; reports
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of H. influenzae causing other soft tissue infection are extremely rare (1). H. influenzae serotype f (Hif), in particular, is an increasingly important cause of invasive disease (3). There are two recent reviews of Hif disease in the literature. First, in 1996, Urwin et al. (3) reviewed 91 cases of invasive Hif infection. Seventy-two percent of these cases occurred in adults, with an overall mortality rate of 30%. A large majority of the patients (78%) had significant underlying comorbidity, most commonly COPD, alcohol abuse, diabetes, or malignancy. Eighty-two percent of cases were infections of the respiratory tract, and there were no reported cases of necrotizing soft tissue infection. More recently, Bruun et al. (4) published a review of 13 cases of invasive Hif disease. Again, respiratory disease was most common (8/13 cases). The other diseases included one each of the following: meningitis, epiglottitis, osteomyelitis, cholangitis, and neutropenic bacteremia without identifiable focus. Again, there were no reported cases of soft tissue infection. In our review, there are only 10 cases of necrotizing fasciitis associated with H. influenzae reported in the literature, 7 of which occurred in adults (Table 1) (2, 5–13). Three cases were secondary to Hif infection, as occurred for our patient. In one of the three reported cases of Hif necrotizing fasciitis, the disease was multifocal in noncontiguous sites, affecting both the upper and the lower extremities (5). This is a distribution of disease similar to that for our patient, with both upper and lower extremities affected. Like our patient, all three patients in the cases reviewed developed signs of severe sepsis and shock complicated by significant thrombocytopenia as well as leukopenia, which can often be seen in severe sepsis caused by Gram-negative bacteria. This information is consistent with the severe systemic illness often manifesting as a complication of necrotizing fasciitis.
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Lower extremity Both lower and upper extremities
Survival to discharge
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very rare, has been reported in the literature and may be an underappreciated disease. When caring for a patient with suspected necrotizing fasciitis, a Gram stain suggestive of this possibility should prompt empirical antimicrobial coverage. It is important to remember that due to this organism’s pleomorphism, Gram stains can often be misinterpreted. Thus, we would suggest that in patients for whom a Gram stain is interpreted as small Gramnegative organisms of any morphology (be it rods, bacilli, or coccobacilli), this diagnosis be considered and antimicrobial therapy that empirically covers this possibility be initiated. While most cases of infection appear to occur in patients less than 2 years or greater than 60 years of age, the infection has been seen in younger individuals. Also, while comorbidities such as diabetes, malignancy, and alcohol abuse may be seen, the infection can also occur in individuals thought to be previously healthy. As is the case with other causes of necrotizing fasciitis, therapy should consist of a combination of antimicrobial therapy and aggressive surgical debridement. REFERENCES 1. Murphy TF. 2009. Haemophilus species (including H. influenzae and chancroid), p 2911–2919. In Mandell GL, Bennett JE, Dolin R (ed), Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, vol 2, 7th ed. Churchill Livingstone, Philadelphia, PA. 2. Hagiya H, Murase T, Naito H, Hagioka S, Morimoto N. 2012. Severe soft tissue infection of the lower extremity caused by Haemophilus influenzae (serotype f, biotype II) in an adult patient. Intern. Med. 51:1783– 1787. http://dx.doi.org/10.2169/internalmedicine.51.7209. 3. Urwin G, Krohn JA, Deaver-Robinson K, Wenger JD, Farley MM. 1996. Invasive disease due to Haemophilus influenzae serotype f: clinical and epidemiologic characteristics in the H. influenzae serotype b vaccine era. The Haemophilus influenzae Study Group. Clin. Infect. Dis. 22:1069 –1076. 4. Bruun B, Gahrn-Hansen B, Westh H, Kilian M. 2004. Clonal relationship of recent invasive Haemophilus influenzae serotype f isolates from Denmark and the United States. J. Med. Microbiol. 53:1161–1165. http: //dx.doi.org/10.1099/jmm.0.45749-0. 5. Resman F, Svensjo T, Unal C, Cronqvist J, Brorson H, Odenholt I, Riesbeck K. 2011. Necrotizing myositis and septic shock caused by Haemophilus influenzae type f in a previously healthy man diagnosed with an IgG3 and a mannose-binding lectin deficiency. Scand. J. Infect. Dis. 43:972–976. http://dx.doi.org/10.3109/00365548.2011.589079. 6. Bush JK, Givner LB, Whitaker SH, Anderson DC, Percy AK. 1984. Necrotizing fasciitis of the parapharyngeal space with carotid artery occlusion and acute hemiplegia. Pediatrics 73:343–347. 7. Chalmers C. 2010. Necrotising fasciitis complicating Haemophilus influenzae type b epiglottitis in an adult. J. Laryngol. Otol. 124:807– 809. http: //dx.doi.org/10.1017/S0022215109992076. 8. Collette CJ, Southerland D, Corrall CJ. 1987. Necrotizing fasciitis associated with Haemophilus influenzae type b. Am. J. Dis. Child. 141:1146 – 1148. 9. Lee EY, Ip WY. 2010. Necrotizing fasciitis of the extremity caused by Haemophilus influenzae serotype b in a healthy adult. Clin. Orthop. Relat. Res. 468:1436 –1439. http://dx.doi.org/10.1007/s11999-009-1126-x. 10. McLellan E, Suvarna K, Townsend R. 2008. Fatal necrotizing fasciitis caused by Haemophilus influenzae serotype f. J. Med. Microbiol. 57:249 – 251. http://dx.doi.org/10.1099/jmm.0.47603-0. 11. Robinson AB, DeWitt EM, Schanberg LE, Moody MA. 2010. Necrotizing fasciitis caused by Haemophilus influenzae type E in a 17-year-old girl with systemic lupus erythematosus. J. Clin. Rheumatol. 16:49 –50. http: //dx.doi.org/10.1097/RHU.0b013e3181c7e095. 12. Saito T, Matsunaga H, Matsumura Y, Segawa H, Takakura S, Nagao M, Iinuma Y, Miyachi Y, Ichiyama S. 2009. Necrotizing fasciitis caused by Haemophilus influenzae type b in an elderly patient. J. Clin. Microbiol. 47:852– 854. http://dx.doi.org/10.1128/JCM.01196-08. 13. Stumvoll M, Fritsche A. 1997. Necrotizing fasciitis caused by unencapsulated Haemophilus influenzae. Clin. Infect. Dis. 25:327. http://dx.doi .org/10.1086/516908. 14. St. Geme JW III, Cutter D, Barenkamp SJ. 1996. Characterization of the
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It is not clear what factors are responsible for predisposition to this rare infection. In our case, one would presume that the infection was likely acquired from the patient’s grandchild. However, how and why the infection then spread to the deep tissues of the extremities is unclear. There is likely a combination of host-specific and/or pathogen-specific factors that create an opportunity for this disease to manifest; however, the nature of these factors remains unclear. In the review of invasive Hif disease by Urwin et al. (3), there was an apparent predilection for hosts with significant underlying comorbidity, 78% of patients having at least one significant medical comorbidity. However, despite a remote history of breast cancer, our patient was otherwise healthy and in excellent physical condition at the time of presentation. Also, in the review of the prior reported cases, at least four were found to have occurred in relatively healthy individuals (5, 7, 9, 12). In one case of a previously healthy man, an IgG3 and mannose-lectin binding deficiency was later discovered, which was thought to have possibly been a predisposing factor (5). However, immune testing of this type is not common practice, and no other reported cases investigated this possibility. According to the review of the literature, this infection does seem to be most common at the extremes of age, with all but three cases occurring in individuals under the age of 2 or over the age of 60. There may be some age-related factors that play a role in the disease, but again, what these may be is not currently clear. In this case, further testing in the laboratory of an expert on Haemophilus disease was done. The isolate was found to be biotype I. Southern analysis showed it to contain the Hsf adhesin gene and the Hap adhesin/invasin gene, both of which are universally present in encapsulated isolates of H. influenzae (14–16). Additionally, no increased cytotoxicity was detected, based on light microscopy and lactate dehydrogenase (LDH) release using in vitro assays with Chang epithelial cells with a prototype H. influenzae type b strain (Eagan) and a prototype nontypeable H. influenzae strain (strain 12) (17). In summary, no unusual factors for increased virulence were detected by this extensive supplementary testing. The mainstay of treatment for necrotizing fasciitis is early surgical intervention. All cases reviewed in the literature were treated with a combined medical and surgical approach. While we certainly advocate life-saving treatment over limb-saving treatment, in our case, we were able to aggressively debride the upper and lower limbs while preserving function by isolating the neurovascular structures from the infectious material initially, allowing extensive removal of skin, subcutaneous tissue, fascia, muscle, and fibrotic material without sacrificing function. In this patient, ipsilateral forequarter and hindquarter amputations were not necessary, but in other cases they may be. Continued postoperative surveillance for residual infection is required, as further returns to the OR may be required even within hours of return from surgery. As with many rare diseases, it is likely that this infection occurs more frequently than what is reported in the literature. Indeed, the relatively high overall survival rate in the reported cases (which would be contrary to the expected overall survival rate in necrotizing fasciitis) would underscore the propensity of reporting bias, with cases with successful outcomes often chosen for publication. As such, it is possible that necrotizing fasciitis due to Haemophilus influenzae, while still a rare entity, does indeed occur more frequently than originally thought. In conclusion, this case highlights several notable and important points. Haemophilus influenzae necrotizing fasciitis, while
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genetic locus encoding Haemophilus influenzae type b surface fibrils. J. Bacteriol. 178:6281– 6287. 15. O’Neill JM, St. Geme JW III, Cutter D, Adderson EE, Anyanwu J, Jacobs RF, Schutze GE. 2003. Invasive disease due to nontypeable Haemophilus influenzae among children in Arkansas. J. Clin. Microbiol. 41: 3064 –3069. http://dx.doi.org/10.1128/JCM.41.7.3064-3069.2003. 16. Omikunle A, Takahashi S, Ogilvie CL, Wang Y, Rodriguez CA, St.
Geme JW III, Adderson EE. 2002. Limited genetic diversity of recent invasive isolates of non-serotype b encapsulated Haemophilus influenzae. J. Clin. Microbiol. 40:1264 –1270. http://dx.doi.org/10.1128/JCM.40.4 .1264-1270.2002. 17. Kehl-Fie TE, St. Geme JW III. 2007. Identification and characterization of an RTX toxin in the emerging pathogen Kingella kingae. J. Bacteriol. 189:430 – 436. http://dx.doi.org/10.1128/JB.01319-06.
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