H1 2009 influenza with multiple organ involvement.
History of Present Illness
An African American man, aged 22 years, was admitted to the hospital with complaints of progressive weakness and hematuria. One week prior to admission, he had begun developing upper respiratory tract symptoms, including rhinorrhea and sore throat, as well as fever and chills. Four days before admission, he started experiencing muscle pain, mainly over his cervical and paraspinal muscles, as well as pain in bilateral legs. He did not take any medications, including over-the-counter pain relievers, for these symptoms.
Past Medical History
No significant past medical history.
He reported that his 4 children (aged 1, 2, 4, and 7 years) experienced similar symptoms preceding the onset of his illness. He denied alcohol or drug use, but he was an active smoker before this illness with 1.5 pack-year smoking history. He worked in a tire shop.
Upon admission to the hospital he was found to be afebrile, with blood pressure of 140/88 mm Hg. He was in no distress, with a clear lung exam, but he was tachycardic, with a heart rate of 105 beats per minute.
Laboratory studies demonstrated white blood cell count 5.9, creatinine (Cr) 1.59 mg/dL (normal range, 0.6-1.3 mg/dL; all subsequent figures in parentheses are normal ranges), calcium ionized 3.3 mg/dL (4.5-5.3 mg/dL), creatine phosphokinase (CPK) 407,176 U/L (24-195 U/L), myoglobin 33,673 ng/mL (17.4-105.7 ng/mL), C-reactive protein (CRP) 7 mg/dL (<0.9 mg/dL). Urinalysis showed zero red blood cells with large hemoglobin and protein of 300 mg/dL. Rapid strep testing of the throat was negative. However, streptozyme was positive. Throat culture collected on the day of admission was negative for group A streptococcal infection. Chest x-ray did not show any infiltrate or acute abnormality, and abdominal CT scan done in the emergency department for hematuria did not demonstrate nephrolithiasis or other abnormalities.
Liver function tests (LFTs) done 6 hours after admission showed aspartate aminotransferase (AST) 1540 U/L (0-41 U/L),alanine aminotransferase (ALT) 286 U/L (0-40 U/L), alkaline phosphatase (ALP) 50 U/L (39-130 U/L), albumin 3.3 g/dL (3.2-5.3 g/dL), and total bilirubin 0.6 mg/dL (0.3-1.2 mg/dL). As part of the workup for acute kidney injury (AKI) by nephrology, all of the following were checked and were negative: thyroid panel, antinuclear antibody, HIV, C and P ANCA, anti–JO-1, complement, and anti-GBM antibody. Uric acid was 10.1 mg/dL (2.6-7.2 mg/dL), and random urine protein was 6260 mg/L with protein (Pr)/Cr ratio of 9.2. Serum protein electrophoresis (SPEP) and urine protein electrophoresis both were negative. Blood cultures and urine culture remained negative. Kidney ultrasound showed normal kidney size and no signs of hydronephrosis. Respiratory culture from the date of admission turned positive for Streptococcus pneumoniae. Due to abnormal LFTs, with AST/ALT ratio more than 2, hepatitis panel was obtained; it reported negative other than positive immunoglobulin G for hepatitis A.
On the day of admission, he noticed red discoloration of the urine along with worsening weakness and muscle pain. He was admitted to the general medical floor with the diagnosis of rhabdomyolysis.
On day 1 of admission, Cr was 2.05 and CPK was 670,516.Both values continued to rise, with hemodialysis initiated when levels were 4.89 (Figure) and 1,271,160 (Table 2), respectively. AST peak was 4100 and ALT peak was 1043, with highest total bilirubin of 0.8 and lowest albumin level of 2.9; ALP stayed within the range of 44 to 51 and gamma-glutamyl transferase was 15 U/L (9-64 U/L). CRP also increased to 17.1 mg/dL.
A respiratory pathogen panel showed positivity for influenza H1 2009, and infectious diseases consultation was obtained. The patient was started on oseltamivir, dose-adjusted based on kidney function. For the positive streptozyme, he received 1 dose of intramuscular benzathine penicillin to prevent complications of probable recent strep infection. The patient received 2 days of intravenous (IV) ceftriaxone for positive S pneumoniae in the sputum; however, this was discontinued as his examination and clinical picture were not consistent with bacterial pneumonia. Nephrology consultation was obtained, and the patient received aggressive intravenous rehydration. The patient was continued on IV fluid therapy with bicarbonate, as well as febuxostat for hyperuricemia. A Foley catheter was placed due to difficulty with mobility secondary to severe muscle pain. Urine output was adequate for the first 3 days of admission. Due to rising Cr and development of dyspnea, the patient was transferred to the intensive care unit on day 4 of admission and was subsequently transferred to a facility with liver transplant capabilities. The patient required intermittent hemodialysis. His CPK and ALT/AST continued to trend downward after the transfer.
Treatment and Follow-up
After 10 days of supportive care and intermittent hemodialysis (HD) for AKI, the patient was readmitted to our facility due to patient preference. He did not require liver transplantation. After return to our facility, CPK was 1433, Cr 6.5, AST 43, ALT 53, albumin 3.4, and total bilirubin 0.6. International normalized ratio (INR) stayed normal for the duration of admission. After 4 days, ALT and AST both returned to normal levels of 33 and 27, respectively
The patient continued to require intermittent HD and was able to be discharged home with follow-up with nephrology and daily labs to direct HD treatment. He did not need any further hemodialysis 20 days after his discharge, and his Cr normalized.
While various viral illnesses can cause rhabdomyolysis, influenza is the most common. The exact mechanism is still not fully known.1-3 Rhabdomyolysis is breakdown of muscle with release of CPK, aldolase, AST, and ALT into the bloodstream.4 In their study, Sellers et al reported 27 cases and a case series of influenza A and B with rhabdomyolysis. The onset of CPK rise was between 1 and 10 days (mean, 7 days); the highest reported CPK was >100,000 U/L, and higher CPK was associated with worse outcomes. Of 27 reported cases, 4 were positive for the H1 2009 strain. Of the 27, 16 had renal failure and 12 required hemodialysis. Ten of the 12 experienced full renal recovery, 1 died, and 1 needed HD beyond hospitalization.5,6-21
Our patient’s initial CPK was 407,176 U/L on the day of admission, which was about 5 days after onset of his upper respiratory symptoms. CPK peaked at 1,271,160 U/L on the fourth day of admission, approximately 9 days after symptom onset. Runnstorm et al reported an association between fever spikes and rise in CPK.4 However, we did not observe any correlation between rise in CPK and fever spikes, as our patient stayed afebrile for the duration of the admission. Mortality is high in influenza-related rhabdomyolysis, especially in the presence of renal failure. In patients who require HD, mortality could approach 40%.21
Acute kidney injury in severe influenza infection is multifactorial, and pigment-induced nephropathy secondary to rhabdomyolysis plays an important role.5 If AKI occurs, it is typically seen early in the disease course. In one study, 78.1 % of patients with severe influenza infection developed AKI less than 72 hours after ICU admission.22 Observational studies reported that the incidence of AKI in such patients ranged from 18% to 66%, with up to 22% requiring HD.5
Our patient developed nonoliguric AKI on the day of admission. Cr continued to rise, and due to the decrease in urine output with no response to diuretic therapy and ensuing volume overload, he was started on and remained on HD with slow but complete recovery of kidney function after discharge. Risk factors for developing AKI include obesity, presence of chronic kidney disease prior to illness, and older age.5,22,23 Our patient had a high BMI (31.82 kg/m2) as a risk factor for AKI in addition to influenza infection.
The underlying mechanism for liver injury in influenza infection is not fully understood.24 Hypoxia with oxygen saturation less than 95% has been reported as a strong risk factor for liver injury.24 In one study, 58% of patients with H1N1 had abnormal liver enzymes.25 Elevation of liver enzymes is reported to be positively correlated with elevation of CRP.24 Zarogoulidis et al reported no difference regarding LFTs in subgroups of their patients with positive or negative H1N1 testing, and the rate of hypoxemia was the same between 2 subgroups. They also reported a 12% prevalence of abnormal LFTs in H1N1-positive patients, which was lower than reported in other studies.26
Our patient had elevated liver enzymes since the day of admission, with AST higher than ALT and with AST peak of 4100 U/L and ALT 1043 U/L on fourth day of admission. Complete normalization occurred within 24 days. We did not observe any change in total bilirubin, INR, or ALP. There was mild decrease in albumin; the lowest level during admission was 2.9 g/dL. Our patient never showed any signs of hypoxemia and did not need oxygen therapy; oxygen saturation stayed >95% during hospitalization.
In conclusion, H1 2009 influenza A can manifest with different extrapulmonary adverse effects and serious consequences. These include rhabdomyolysis, secondary AKI, and severe elevation in liver enzymes; all must be monitored closely and treated accordingly. Paying close attention to the potential development of these adverse effects can prevent further morbidity and mortality of influenza H1 2009.
Khorsand Askari is an internal medicine physician at Community Health Services in Fremont, Ohio. and a former infectious diseases fellow at the University of Toledo Medical Center, Toledo, Ohio.
Shabpiray is an internal medicine resident at the University of Toledo Medical Center, Toledo, Ohio.
Deering is an assistant professor of medicine and associate program director of the Infectious Diseases Fellowship at the University of Toledo Medical Center, Toledo, Ohio.